2-arylacetic acids, their derivatives and pharmaceutical compositions containing them

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to new use of compounds of 2-arylacetic acid and amides with formula (I) and their pharmaceutically used salts, where A comprises an atom X and is phenyl or a 5-6 member heteroaromatic ring, optionally containing a heteroatom, chosen from N; corresponding positions on ring A are marked by numbers 1 and 2; atom X is chosen from N (nitrogen) and C (carbon); R represents a substituting group on ring A, chosen from: a group in 3 (meta) positions, chosen from a group comprising straight or branched C1-C5-alkyl, C2-C5-acyl; a group in 4 (para) positions, chosen from a group, comprising C1-C5-alkyl, C1-C5-alkanesulphonylamino, substituted with halogens; Hy represents a small hydrophobic group with steric inhibition constant ν between 0.5 and 0.9 (where ν is Charton steric constant for substitutes), comprising methyl, ethyl, chlorine, bromine, group Y chosen from O (oxygen) and NH; when Y represents O (oxygen), R' represents H (hydrogen); when Y represents NH, R' is chosen from groups: -H, - residue with formula SO2Rd, where Rd represents C1-C6-alkyl. The invention can be used in making medicinal agents, which are inhibitors of induced IL-8 PMN chemotaxis (CXCR1) or induced GRO-α PMN chemotaxis (CXCR2).

EFFECT: new use of compounds of 2-arylacetic acid and amides and their pharmaceutically used salts.

14 cl, 2 tbl, 44 ex, 4 dwg

 

Brief description of the invention

The present invention relates to 2-allakazham acids and their derivatives, containing pharmaceutical compositions, which are used for prevention and treatment of tissue damage due to complicated recruitment polymorphonuclear neutrophil (PMK cells) at the site of inflammation. In particular, the invention relates to 2-phenylacetic acid and its derivatives, used for the treatment of IL-8 mediated diseases, such as psoriasis, ulcerative colitis, COPD, and disorders caused by ischemia and reperfusion.

Background of invention

Chemical stimulation (stimulating substances called chemokines) reacting a specific blood cells (macrophages, granulocytes, neutrophils, polymorphonuclear), migrating along the concentration gradient stimulating agent in a process called chemotaxis. Main known stimulating agents or chemokines presents the breakdown products of complement Sa, some N-formylpiperidine formed by the lysis of the bacterial surface, or peptides synthetic origin, such as formulationacupunture (f-MLP), and mainly by a number of cytokines, including interleukin-8 (IL-8, also known as CXCL8). Interleukin-8 is an endogenous chemotactic factors the PRS, formed by most nuclear cells, such as fibroblasts and macrophages. In some pathological conditions characterized complicated by the recruitment of neutrophils, more severe tissue damage at the site is associated with infiltration of polymorphonuclear cells. Recently it was widely covered the role of neutrophil activation when determining damage associated with postischemic reperfusion 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 on the surface of human neutrophils, and certain types of T-cells (L. Xu et al., J. Leukocyte Biol., 57, 335, 1995). Known selective ligands that can recognize between CXCR1 and CXCR2: GRO-α is an example of CXCR2 selective chemotactic factor.

The potential pathogenic role of IL-8 in lung diseases (pneumonia, acute respiratory diseases, asthma, chronic lung inflammation and fibrosis cystitis) and especially in pathogenesis COPD (chronic obstructive pulmonary disease) via CXCR2 detail (D. WP Hay and H.M.Sarau., Current Opinion in Pharmacology 2001, 1:242-247).

Characteristic neutrophilic accumulation occurs in acute and chronic pathological condition, for example in the ilen inflamed and resistant to therapy areas of psoriatic lesions. The neutrophil chemotactic are attracted and activated due to the synergistic action of chemokines, IL-8 and Gro-α, secreted by stimulated keratinocytes, as well as C5a/C5a-desArg fraction formed in the complementary alternative activation (T.Terui et al., Exp. Dermatol., 9, 1, 2000).

New classes of potent and selective inhibitors of the biological activity of IL-8 (amides R-2-arylpropionic acid and N-arylsulfonamides) described as effective inhibitors induced IL-8 neutrophil chemotaxis and degranulation (WO 01/58852; WO 00/24710). It also describes new subclasses of R and S 2-phenylpropionic acids (WO 03/043625) as potent inhibitors of IL-8, completely devoid of unwanted inhibitory effect of the enzyme cyclo-oxygenase (CSC). Inhibition of prostaglandin synthesis due to inhibition of CSCS, in fact, includes an increase in the formation of cytokines, which leads to increased unwanted Pro-inflammatory effects of neutrophils.

Detailed description of the invention

Research medicinal chemistry showed a significant role of the methyl group on propionic chain 2-arylpropionic acids in the manifestation of their inhibition of IL-8 steps.

The inventors have indeed shown that 2-[4-isobutylphenyl]acetic acid (ibufenac) and 2-[3-benzoylphenyl]acetic acid (Cetop the NAC), well-known inhibitors CSC belonging to the family of phenylacetic acid, do not show any inhibition of IL-8 steps, which, in contrast, is manifested in strong relevant phenylpropionic acids, such as ibuprofen and Ketoprofen.

Usually 2-phenylacetic acids and their derivatives, such as amides and sulfonamides, absent any inhibition of IL-8 action, and this confirms the essential role of methyl groups in the respective 2-phenylpropionic derivatives.

The authors of the present invention was completed SAR studies on various classes of 2-arylpropionic acids and derivatives, described above, which allowed us to identify pharmacophore structure inherent in all of these new classes ihibitors IL-8.

Pharmacophore is defined as the combination of steric and electronic requirements for the class of biologically active compounds that are required for biological activity; usually pharmacophore can be seen as a combination of steric and electronic requirements necessary to ensure positive interactions between biologically active molecule and its target. The assumption in the study of pharmacophore, is that all compounds in the training sequence share the same mechanism and interact with the same biological the practical target.

The inventors have identified two pharmacophore models: the first model, providing the biological activity of inhibitors of IL-8, selectively acting on CXCR1-mediated path of metabolism (hereinafter CXCR1 inhibitors), and in the second model, representing the steric and electronic recruiting inhibitors of IL-8 , dual acting on indirect CXCR1 and CXCR2 pathway of metabolism (hereinafter CXCR1/CXCR2 inhibitors). These two models are responsible for the observed dependence of activity from patterns, because all tested inactive molecules across two full pharmacophoric hypotheses or are no significant signs of overlay (unsuitable), or meet pharmacophoric hypothesis in high-energy conformations. Two newly found pharmacophoric models share four respectively five and six signs; these four characteristics of a fully combined in the chemical space 3D. The scheme of the General part of pharmacophoric models are shown in figure 1.

Description of the drawings

Figure 1 graphically shows the four General feature of pharmacophores respectively inhibitors CXCR1 and inhibitors CXCR1/CXCR2. The following types of distinctive signs are pharmacophore part: two acceptor hydrogen bonds, one aromatic hydrophobicity and one aliphatic hydrophobic. hydrophobia part (aromatic and aliphatic) are represented by spheres with a radius of 1.7 angstroms. The acceptor of hydrogen bonds represented by a vector function consisting of two spheres whose centers of gravity are at 3.0 Angstrom. Smaller (radius of 1.7 angstroms) field defines the position of the atom acceptor of hydrogen bonds in the ligand, and the larger sphere (2.3 angstroms) defines the projection point of the hydrogen bond acceptor from the receptor. The solid area represents the exact location in 3D space of a methyl group phenylpropionamide balance.

Figure 2 presents the imposition of the following arylpropionic derivatives:

R(-)2-(4-isobutylphenyl)propionic acid; R(-) 2-(4-isobutylphenyl)propionylthiocholine; R(-)-N-(2'-hydroxyethoxymethyl)-2-(4-isobutylphenyl)propionate. The solid area represents the exact location in 3D space of a methyl group phenylpropionamide balance.

Figure 3 presents the imposition of the following alloxanic derivatives: (2-methyl-4-isobutylphenyl)acetic acid; (2-methyl-4-isobutylphenyl)acetylethanolamine; (2-methyl-4-isobutylphenyl)ndimethylacetamide.

Figure 4 shows the overlay of the following alloxanic derivatives: (5-benzoyl-1-methyl-1H-pyrrol-2-yl)acetic acid; (1-benzoyl-2-methyl-1H-indol-3-yl)acetylethanolamine; (2-chloro-3-benzoylphenyl)ndimethylacetamide.

On the doctrine of pharmacophore was carried out using the software Catalyst ™, version 4.7 (Molecular Simulations, Inc., San Diego, CA), which is intended to identify the General configuration of the active molecules according to their chemical characteristics. A configuration is a set of relative positions in 3D space, each associated with a type of sign. All compounds in the training sequence are described in terms of their chemical functions related to 3D space. In addition, each chemical fragment can be considered as more than one characteristic, on the basis of the set of similarity. For example, the aromatic ring can install both hydrophobic interactions and π-π interactions in the target node, and this different behavior is attributed to various characteristics (hydrophobic, hydrophobic, aromatic). Functional group in the molecule may be associated with more than one sign, depending on its chemical and physical properties, and different functional groups may exhibit similar properties when interacting with the purpose, charting thus the same sign.

Analysis of the definitions, characteristics and choice of features represent a crucial stage in the development of the hypothesis of pharmacophore. It is well known that the most important forces included in molecular recognition, presented by electrostatic interactions, hydrogen bonds and hydrophobic cooperation is modestiae. The inventors have adopted the definition of several features related to the chemical nature of the group's ability to carry out specific interactions responsible for the biological activity.

Signs of

The hydrogen bond acceptor (ABC) (lipid)

The sign associated with the lipid acceptor hydrogen bonds, characterized by the following types of atoms or groups of atoms, which are available with surface atoms of nitrogen, oxygen or sulfur (except for the atoms of higher valency), which have one pair, and the charge is less than or equal to zero.

Since this is a lipid environment, all primary amines (primary, secondary and tertiary) is included in the definition. Hydrogen bond is a highly directional interaction, this characteristic is indirectly linked to theoretical position of the respective donor of hydrogen. Position three hydrogen bonds are considered, for example, a carbonyl group (acceptor), the first two along the ideal of the provisions of the single pairs, and the third is along the direction of the C=O.

Hydrophobic (aliphatic, aromatic)

Sign hydrophobicity is defined as a continuous set of atoms that are not adjacent with any concentration of charge (charged atoms or electronegative and what Ohm), in conformational variant of the structure in which the atoms are surface available, including phenyl, cycloalkyl, isopropyl and methyl.

However, it was necessary to distinguish between the characteristic aromatic hydrophobicity of the character aliphatic hydrophobicity to establish a satisfactory correlation with biological results. The first considers only the aromatic atoms, the latter considers only the aliphatic atoms.

It is believed that the molecule corresponds to the configuration only if it has a set of relative characteristics and specific conformation, so that its characteristics can be superimposed on the corresponding "ideal" position. The set of features can be considered as imposed if each sign is within a particular distance with respect to access from the ideal point.

The absolute coordinates spherical centroid of each characteristic are listed below:

Aromatic hydrophobicity has Cartesian coordinates +2,588; +0,613; -1,940 respectively along the axes XYZ.

Aliphatic hydrophobicity has Cartesian coordinates +1,788; +2,693; +1,260 respectively along the axes XYZ.

Projected point 1 acceptor hydrogen bonds has Cartesian coordinates -2,713; +2,333; +2,840 respectively along the axes XYZ.

Position 1 acceptor hydrogen bonds has Cartesian coordinates -0,23; 0,936, +1,877 respectively along the axes XYZ.

Projected point 2 of the hydrogen bond acceptor (optional) is the Cartesian coordinates

-5,013; -1,188; -0,400 respectively along the axes XYZ.

The starting point of the 2 hydrogen bond acceptor (optional) is the Cartesian coordinates

-2,688; -1,514, +1,472 respectively along the axes XYZ.

Mapping the first three signs (aliphatic hydrophobicity, aromatic hydrophobicity, hydrogen bond acceptor 1) is crucial for biological inhibiting IL-8 activity class; the fourth sign (acceptor hydrogen bonds 2) can be optionally mapped molecules of class, but the presence of acceptor hydrogen bonds of the second group is not necessary.

All distances between the chemical characteristics established tolerances +0.5 angstroms and all geometric angles are tolerances of ± 20 degrees.

As discussed above, may have different pharmacophoric points to complete pharmacophoric analysis, but their description is not relevant to the subject matter of the present invention. The observed CXR1/CXR2 selectivity in the class is strictly related to the ability of inhibitors to correspond to specific points in neoba part of pharmacophore.

On the contrary, if we are talking about the General part of pharmacophore, the General principle of superposition is observed for inhibitors CXR1 and ing is beterov CXR1/CXR2, belonging to classes 2-phenylpropionic acid, 2-phenylpropionaldehyde and 2-phenylpropionamide, as shown in figure 2. Solid areas represent the exact location in 3D space of methyl groups phenylpropionamide fragment.

In the recovered ligands, which are partially or fully Carteret this hypothesis (figure 2), phenyl residue 2 phenylpropionate chemical structures are always very well correspond to the characteristic aromatic hydrophobicity; the sign of acceptor hydrogen bonds (ABC) 1 fairly well supported by the carbonyl oxygen propylaniline residue; the sign of acceptor hydrogen bonds (ABC) 2 is not necessarily confirmed by the atom of the second hydrogen bond acceptor on the balance connected with amide or sulfonamidnuyu nitrogen; sign aliphatic hydrophobicity is evident methyl group propylaniline balance. Phenylacetic acid and its derivatives in the light of the above considerations do not meet pharmacophoric hypothesis, because a defining characteristic of aliphatic hydrophobicity, represented by a solid sphere in figure 2, is not present in the chemical structure.

The inventors have determined that the selected subclasses of 2-alloxanic acids and their derivatives, which do not contain a methyl group in propionyl residue, show unexpected is th ability to effectively inhibit mediated IL-8 chemotaxis and degranulation of neutrophils.

Thus, the present invention relates to the use of compounds 2-akriluksusnoy acids and derivatives of formula (I):

and their pharmaceutically acceptable salts,

where

And includes the atom X and is a 5-6-membered aromatic or heteroaromatic ring, optionally containing a heteroatom, or an additional heteroatom, when X is N, selected from N (nitrogen), O (oxygen), S (sulfur); 5-6-membered aromatic or heteroaromatic ring optionally condensed with a second ring with the formation of billionsof aromatic or heteroaromatic structures;

figures 1 and 2 marked with the relevant provisions of the ring A;

atom X is selected from N (nitrogen) and C (carbon);

R means the replacement group on the ring And selected from:

- group 3 (meta) position selected from the group: a straight or branched C1-C5alkyl, C2-C5alkenyl or2-C5-quinil, substituted or unsubstituted phenyl, straight or branched C1-C5hydroxyalkyl,2-C5-acyl, substituted or unsubstituted benzoyl;

group in the 4 (para) position selected from the group:1-C5-alkyl, C2-C5alkenyl or2-C5-quinil,3-C6-cycloalkyl,1-C5-acyloxy, Sames the config or unsubstituted benzoyloxy, With1-C5-acylamino, substituted or unsubstituted benzoylamine,1-C5-sulfonyloxy, substituted or unsubstituted, benzosulfimide,1-C5-alkanesulfonyl, substituted or unsubstituted, benzosulfimide,1-C5-alkanesulfonyl, substituted or unsubstituted benzosulfimide, 2-furyl; 3-tetrahydrofuryl; 2-thiophenyl; 2-tetrahydrothiophene or1-C8-alkanoyl, cycloalkenyl or arylalkyl-C1-C5-alkylamino;

Hy represents a small hydrophobic group with a value of the coefficient of steric difficulties ν in the interval between 0.5 and 0.9 E (where ν is the steric constant Carton (Charton steric constant) for alternates), including methyl, ethyl, chlorine, bromine, methoxy, trifluoromethyl;

the group Y is selected from O (oxygen) and NH;

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

when Y represents NH, R' is selected from groups:

-H, C1-C5-alkyl, C1-C5-cycloalkyl,1-C5alkenyl;

-residue amino acids, including straight or branched C1-C6-alkyl, C1-C6-cycloalkyl,1-C6alkenyl, phenylalkyl substituted by one or more carboxy (COOH) groups;

- residue amino acids, including straight or branched C1-C6-alkyl, C -C6-cycloalkyl,1-C6alkenyl, phenylalkyl containing in the chain heteroatom selected from oxygen and sulfur, and one or more carboxy (COOH) groups;

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

-residue of the formula -(CH2)n-NRaRb, where n means an integer from 0 to 5 and each of the radicals Ra and Rb, which may be identical or different, represents a C1-C6-alkyl, C1-C6alkenyl or alternative radicals Ra and Rb together with the nitrogen atom to which they are attached, form a 3 - to 7-membered heterocycle of formula (II)

where W stands for simple communication, CH2, O, S or N-Rc, where Rc denotes H, C1-C6-alkyl or C1-C6-alkylphenyl;

- balance OR", where R ' denotes H, methyl, carboxymethyl;

- residue formula SO2Rd, where Rd denotes1-C6-alkyl, C1-C6-cycloalkyl,1-C6alkenyl;

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

Aromatic ring And may be optionally substituted by additional groups, such as1-C5-alkyl or halogen.

The term "samisen is th" in the above definitions means the residue, substituted by a group selected from among groups such as1-C5-alkyl, halogen, hydroxy, C1-C5-alkoxy, amino, C1-C5-alkylamino, nitro or cyano.

Preferred And groups in the compounds of formula (I) are aromatic or heteroaromatic ring, selected from among groups such as benzene, naphthalene, pyridine, pyrimidine, pyrrole, imidazole, furan, thiophene, indole and 7-Aza-indole.

Preferred compounds of formula (I) are those in which the group YR' means OH;

preferred R' groups, when Y represents NH, are:

- amino acid residue of glycine, β-alanine, γ-aminobutyric acid or residues of L-α-amino acid selected from the group of L-alanine, valine, leucine, isoleucine, nor-leucine, phenylalanine, S-methylcysteine, methionine;

- the remainder of the formula-CH2-CH2-O-(CH2-CH2O)R", where R ' denotes H or C1-C5-alkyl;

- the remainder of the formula -(CH2)n-NRaRb, where n means 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 remainder OR'in which R' denotes H, methyl;

the remainder of the formula SO2Rd, where Rd denotes methyl, ethyl or isopropyl.

Preferred R groups in the compounds of formula (I) are 3'-benzo is l, 3'-(4-chlorbenzoyl), 3'-(4-methylbenzoyl), 3'-acetyl, 3'-propionyl, 3'-Isobutanol, 3'-ethyl, 3'-isopropyl, 4'-isobutyl, 4'-tripterocalyx, 4'-benzosulfimide, 4'-triftormetilfullerenov, 4'-benzosulfimide, 4'-benzosulfimide, 4'-atomic charges, 4'-propionyloxy, 4'-benzoyloxy, 4'-acetylamino, 4'-propionamido, 4'-benzoylamine.

The preferred Hy groups in compounds of formula (I) are methyl, ethyl, chlorine, bromine, methoxy, trifluoromethyl.

Especially preferred is the use of compounds selected from among the following:

(3-benzoyl-2-were)acetic acid

(2-chloro-3-propionitrile)acetic acid

(3-isopropyl-2-were)acetic acid

(4-isobutyl-2-were)acetic acid

{2-methyl-4-[(phenylsulfonyl)amino]phenyl}acetic acid

{2-methyl-4-[(trifloromethyl)amino]phenyl}acetic acid

{2-chloro-4-[(trifloromethyl)oxy]phenyl}acetic acid

(5-acetyl-1-methyl-1H-pyrrol-2-yl)acetic acid

[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetic acid

(5-benzoyl-1-methyl-1H-pyrrol-2-yl)acetic acid

[1-methyl-5-(4-chlorobenzoyl)-1H-pyrrol-2-yl]acetic acid

(5-isobutyryl-1-methyl-1H-pyrrol-2-yl)acetic acid

(1-benzoyl-2-methyl-1H-pyrrol-3-yl)acetic acid

(1-benzoyl-2-chloro-1H-pyrrol-3-yl)acetic acid

(1-benzoyl-2-methyl-H-indol-3-yl)acetic acid

[1-(4-chlorobenzoyl)-2-methyl-1H-indol-3-yl]acetic acid

(1-isopropyl-2-methyl-1H-pyrrol[2,3-b]pyridine-3-yl)acetic acid

(3-benzoyl-2-methoxyphenyl)acetic acid

(5-acetyl-1-methyl-1H-pyrrol-2-yl)ndimethylacetamide

(5-acetyl-1-methyl-1H-pyrrol-2-yl)-N-carboxymethylated

(S)(5-acetyl-1-methyl-1H-pyrrol-2-yl)-N-(2-carboxyethyl) ndimethylacetamide

(5-acetyl-1-methyl-1H-pyrrol-2-yl)-N-(3-dimethylaminopropyl) ndimethylacetamide

(S)(5-acetyl-1-methyl-1H-pyrrol-2-yl)-N-(1-carboxy-2-methoxyethyl)ndimethylacetamide

(4-isobutyl-2-were)ndimethylacetamide

(2-chloro-3-propionitrile)-N-(3-dimethylaminoethyl)ndimethylacetamide

(3-isopropyl-2-were)-N-[3-(1-piperidinyl)propyl]ndimethylacetamide

(3-benzoyl-2-were)ndimethylacetamide

(1-benzoyl-2-methyl-1H-indol-3-yl)ndimethylacetamide

(1-benzoyl-2-methyl-1H-indol-3-yl)-N-(3-dimethylaminopropyl)ndimethylacetamide

[1-(4-chlorobenzoyl)-2-methyl-1H-indol-3-yl]ndimethylacetamide

[1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]ndimethylacetamide

{2-chloro-4-[(trifloromethyl)oxy]phenyl}-N-(2-hydroxyethoxyethyl)ndimethylacetamide

(1-benzoyl-2-methyl-1H-pyrrol-3-yl)-N-(2-methoxyethyl)ndimethylacetamide

(1-benzoyl-2-chloro-1H-pyrrol-3-yl)-N-[3-(1-morpholino)propyl]ndimethylacetamide

(5-isobutyryl-1-methyl-1H-pyrrol-2-yl)ndimethylacetamide

(5-benzoyl-1-methyl-1H-pyrrol-2-yl)-N-(2-carboxymethyl)ndimethylacetamide

[1-methyl-5-(4-chlorobenzoyl)-1H-pyrrol-2-yl]-N-(2-hydroxyethoxyethyl)ndimethylacetamide

[1-methyl-5-(4-chlorobenzoyl)-1H-pyrrol-2-yl]ACET the MFA

{2-methyl-4-[(phenylsulfonyl)amino]phenyl}-N-(3-dimethylaminopropyl)ndimethylacetamide

(3-benzoyl-2-methoxyphenyl)ndimethylacetamide.

The present invention also relates to new 2-allakazham acids and derivatives of formula (Ia)

and their pharmaceutically acceptable salts;

where:

And includes the atom X and is a 5-6-membered aromatic or heteroaromatic ring, optionally including a heteroatom, or an additional heteroatom, when X is N, selected from N(nitrogen), O (oxygen), S (sulfur); and 5-6 membered aromatic or heteroaromatic ring optionally condensed with a second ring with the formation of the bicyclic aromatic or heteroaromatic structures;

figures 1 and 2 marked with the relevant provisions of the ring A;

atom X is selected from N (nitrogen) and C (carbon);

R means the replacement group on the ring And selected from:

- group 3 (meta) position selected from the group: a straight or branched C1-C5alkyl, C2-C5-alkenyl or2-C5-quinil, substituted or unsubstituted phenyl, straight or branched C1-C5hydroxyalkyl,2-C5-acyl, substituted or unsubstituted benzoyl;

group in the 4 (para) position selected from the group:1-C5alkyl, C2-C5alkenyl or 2-C5-quinil,3-C6-cycloalkyl,1-C5-acyloxy, substituted or unsubstituted benzoyloxy,1-C5-acylamino, substituted or unsubstituted benzoylamine,1-C5-sulfonyloxy, substituted or unsubstituted, benzosulfimide,1-C5-alkanesulfonyl, substituted or unsubstituted, benzosulfimide,1-C5-alkanesulfonyl, substituted or unsubstituted benzosulfimide, 2-furyl; 3-tetrahydrofuryl; 2-thiophenyl; 2-tetrahydrothiophene or1-C8-alkanoyl, cycloalkenyl or arylalkyl-C1-C5-alkylamino, such as acetyl-N-methylamino, pivaloyl-N-ethylamino.

Hy represents a small hydrophobic group with a value of the coefficient of steric difficulties ν in the interval between 0.5 and 0.9 E (where ν is the steric constant Carton (Charton) for alternates), including methyl, ethyl, chlorine, bromine, methoxy, trifluoromethyl;

Rd means1-C6-alkyl, C1-C6-cycloalkyl,1-C6alkenyl.

Preferred compounds of formula (Ia) are those in which a represents a benzene, pyridine, pyrimidine, pyrrole, imidazole, furan, thiophene, indole;

Rd represents a methyl, ethyl or isopropyl;

Hy is selected from methyl, ethyl, chlorine, bromine, methoxy, trifloromethyl.

About obinna preferred compounds of the present invention are:

(5-acetyl-1-methyl-1H-pyrrol-2-yl)acetyl methanesulfonamide

(4-isobutyl-2-were)acetyl methanesulfonamide

{2-methyl-4-[(trifloromethyl)amino]phenyl}acetyl methanesulfonamide

[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetylethanolamine.

The compounds of formula (Ia)in which Rd is above the values obtained by converting the compounds of formula (I)in which YR' IT means, in reactive intermediate compound, such as allalone, preferably acylchlorides, or known "active ester", preferably benzotriazolyl ester, and their interactions with the compound of the formula NH2SO2Rd in the presence of a suitable base, preferably tert-butoxide potassium. Compounds according to the invention, despite the absence of a methyl group on propionic chain, are effective and selective inhibitors of PMN chemotaxis of human-induced IL-8.

As discussed above, molecules that do not contain the above-mentioned methyl group on the chiral carbon atom propionic chain, tend to be inactive in the test-induced IL-8 chemotaxis due to the key role of methyl groups in the mapping characteristic aliphatic hydrophobicity of pharmacophore.

The General character of the blend of compounds according to izopet is of the hypothesis pharmacophore, described above and presented in figure 1, is shown in figure 3 and 4.

Figure 3 shows the overlay of the following compounds belonging to the class alloxanic derivatives: (2-methyl-4-isobutylphenyl)acetic acid; (2-methyl-4-isobutylphenyl)acetylethanolamine; (2-methyl-4-isobutylphenyl)ndimethylacetamide.

Figure 4 shows the overlay of the following compounds belonging to the class alloxanic derivatives: (5-benzoyl-1-methyl-1H-pyrrol-2-yl)acetic acid; (1-benzoyl-2-methyl-1H-indol-3-yl)acetylethanolamine; (2-chloro-3-benzoylphenyl)ndimethylacetamide.

Compounds of the present invention possess strong biological activity due to the unexpected properties of the hydrophobic group (Hy) in regulation 2 (formula I) accurately reflect the characteristic of aliphatic hydrophobicity model pharmacophore, represented by a solid spheres in figure 3 and 4. The General character overlay pharmacophore indeed observed for compounds of formula (I). Hydrophobic group (Hy) restored ligands, which are partially or fully Carteret this hypothesis, always confirm the sign aliphatic hydrophobicity (solid sphere, figure 3). In addition, the compounds of formula (I) show the required conformational arrangement of functional groups in order to fully or partially to map other point pharmacophoric hypotheses in the low-energy convo the information.

Compounds of the present invention have a great advantage due to the absence of chiral carbon atom relative to the known inhibitors of IL-8, owned by the family of 2-arylpropionic acids and their derivatives. The method of obtaining and purification known 2-arylpropionic acids and their derivatives really requires the development of complex enantioselective conditions or the introduction stage optical resolution with consequent undesirable increase in the cost of the active element.

Compounds of the present invention of formula (I) and (Ia) are usually isolated in the form of additive salts, both organic and inorganic pharmaceutically acceptable acids and bases.

Examples of the above-mentioned acids selected from among such acids as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonate acid, fumaric acid, citric acid.

Examples of the above-mentioned bases selected from among such bases as sodium hydroxide, potassium hydroxide, calcium hydroxide, (D,L)-lysine, L-lysine, tromethamine.

Compounds of the present invention of formula (I) tested in vitro for their ability to inhibit chemotaxis of polymorphonuclear leukocytes (hereinafter PMN) and monocytes induced by fractions of IL-8 and GRO-α. For this purpose, to highlight PMN from heparinization human blood, mononucleate removed, sit the orientations on the dextran (by the way, open W.J. Ming et al., J. Immunol., 138, 1409, 1987) and red blood cells - hypotonic solution. Cell viability was calculated by exclusie of Triana (Trypan blue, and the ratio of circulating polymorphonuclear was assessed by cell centrifugate after dyeing Diff Quick.

Human recombinant IL-8 (Pepro Tech) was used as a stimulating agent in the chemotaxis experiments with obtaining almost identical results: the lyophilized protein was dissolved in a volume of HBSS containing 0.2% bovine serum albumin (BSA), to thereby obtain a basic solution having a concentration of 10-5M intended for dilution with HBSS to a concentration of 10-9M, for samples on chemotaxis.

When carrying out tests on chemotaxis (according to W. Falket et al., J. Immunol. Methods, 33, 239, 1980) was used containing no PVP filters with a porosity of 5 μm and microcamera suitable for replication.

Compounds of the present invention of formulas (I) and (Ia) were evaluated in the concentration range between 10-6and 10-10M; for this purpose they were added in the same concentration as on the bottom of the pores, and on the top of the pores microcamera. The ability of the compounds of the present invention of formula I to inhibit induced IL-8 chemotaxis of human monocytes was performed in accordance with the method described by Van Damme J. et al.(Eur. J. Immunol., 19, 2367, 189).

Especially preferred is the use of compounds of formula (I), in which the group R represents a 3'-benzoyl, 3'-(4-chlorbenzoyl), 3'-(4-methylbenzoyl), 3'-acetyl, 3'-propionyl, 3'-Isobutanol, 4'-tripterocalyx, 4'-benzosulfimide, 4'-triftormetilfullerenov, 4'-benzosulfimide, 4'-benzosulfimide, 4'-atomic charges, 4'-propionyloxy, 4'-benzoyloxy, 4'-acetylamino, 4'propionamido, 4'-benzoylamine; this activity allows the use of these compounds in the treatment associated with IL-8 pathology when CXCR2 pathway or in combination with a signal transmission CXCR1. Dual inhibitors of IL-8 and GRO-α-induced biological activities are highly preferred from the viewpoint of therapeutic applications, but described compounds acting selectively on CXCR1, IL-8 receptor or receptor CXCR2 GRO-α/IL-8 receptor, can find useful therapeutic applications in the treatment of specific pathology, as described below.

Biological activity of compounds showing high efficiency and as inhibitors induced IL-8 of PMN chemotaxis (CXCR1), and as dual inhibitors induced IL-8 and GRO-α of PMN chemotaxis (CXCR1/CXCR2), are presented in table 1.

Table 1
Data on biological activity in the CXCR1 and CXCR2 receptors (% inhibition)
ConnectionIL-8 (c=10-8M)GRO-α (c=10-8M)
(5-isobutyryl-1-methyl-1H-pyrrol-2-yl)acetic acid58±1165±11
(5-acetyl-1-methyl-1H-pyrrol-2-yl)acetic acid60±765±5
(5-acetyl-1-methyl-1H-pyrrol-2-yl)ndimethylacetamide54±1044±9
(5-acetyl-1-methyl-1H-pyrrol-2-yl)acetylethanolamine50±1046±14
(4-isobutyl-2-were)acetic acid60±104±8
(3-isopropyl-2-were)acetic acid62±85±10
(4-isobutyl-2-were)acetylethanolamine67±140±10
(2-chloro-3-propionitrile)acetic acid67±14 27±8
{2-methyl-4-[(trifloromethyl)amino]phenyl}
acetylethanolamine
60±752±5

All compounds of the present invention showed a high degree of selectivity relative to the inhibition induced IL-8 chemotaxis compared with chemotaxis induced by C5a(10-9M) or f-MLP(10-8M).

It is established that the compounds of formula (I) and (Ia) is completely ineffective as inhibitors of the enzyme cyclooxygenase (CSC). In most cases, the compounds of formula (I) are not involved in the formation of PGE2induced in murine macrophages by stimulation of lipopolysaccharide (LPS, 1 μg/ml) at a concentration of between 10-5and 10-7M. Inhibition of education PGE2that can be recorded, often occurs at the limit of statistical significance and is below 15-20% of base value. Reduced efficiency of inhibition of CSCS is an advantage for therapeutic use the compounds of the present invention, since the inhibition of prostaglandin synthesis is a stimulus for macrophage cells to multiply the synthesis of TNF-α (induced by LPS or hydrogen peroxide), which is an important mediator of neutrophil activation and stimulus for the formation of interleukin who -8 cytokine.

In light of the experimental evidence discussed above, and the role of interleukin-8 (IL-8) and related compounds in processes including the activation and infiltration of neutrophils, the compounds of the present invention is particularly suitable for use in the treatment of diseases such as psoriasis (R.J. Nicholoff et al., Am. J. Pathol., 138, 129,1991). Other diseases that can be treated using compounds of the present invention, are chronic inflammatory intestinal disorders such as ulcerative colitis (Y.R. Mahida et al., Clin. Sci., 82, 273,1992), and melanoma, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis (M.Selz et al., J. Clin. Invest., 87, 463,1981), idiopathically fibrosis (E. J. Miller, cited above, 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 lesions caused by ischemia and reperfusion.

Inhibitors of activation of CXCR1 and CXCR2 are widely used, as discussed in detail above, particularly in the treatment of chronic inflammatory pathologies (e.g., psoriasis), in which activation of both receptors IL-8 plays a crucial pathophysiological role in the development of the disease.

In fact, it is known that activation of CXCR1 important when mediated IL-8 the PMN chemotaxis (Hammond M et al., J. Immunol., 155, 1428, 1995). On the other hand, one expects the tsya, the activation of CXCR2 important when mediated IL-8 epidermal cell proliferation and angiogenesis psoriatic patients (R. Kulke Et al., J. Invest. Darmatol., 110, 90, 1998).

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

Therefore, another objective of the present invention relates to the use of compounds of formula (I) and (Ia) in the manufacture of a medicinal product 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 damages caused by ischemia and reperfusion. The invention also relates to compounds of formula (Ia) for use as pharmaceuticals.

Pharmaceutical compositions comprising compounds of the present invention and a suitable carrier for him, also included in the scope of claims of the present invention.

Compounds of the present invention together with traditionally used additives, carrier, diluent or excipient may actually be in the form of pharmaceutical compositions and unit dosages and in this form is to be applied as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, Alexiy or capsules filled with love, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous) administration. Such pharmaceutical compositions and unit dosage forms may include ingredients in conventional proportions, with or without additional active compounds or elements, and such unit dosage forms may contain any suitable effective amount of the active ingredient, suitable intended for reception interval daily doses.

When used as pharmaceuticals alloxane acid of the present invention and derivatives thereof are usually administered in the form of pharmaceutical compositions. Such compositions can be obtained by a method well known in the pharmaceutical industry and includes at least one active connection. Typically, compounds of the present invention is administered in a pharmaceutically effective amount. The number of real input connection will typically be determined by the physician, taking into account the surrounding circumstances, including the subject to the treatment condition, the chosen route of administration, the actual entered the compound, the age, weight and response of the particular patient, the severity of the patient's symptoms, etc.

The pharmaceutical compositions of the present invention can be introduced in various ways, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and vnutriskalnyh. Depending on the intended method of administration of the compounds preferably are in the form of solutions for injection, or in the form of oral compositions. Compositions for oral administration can be in the form of the main volume of solution or suspension, or bulk powders. However, more accepted, the compositions were presented in the form of single doses to facilitate accurate dosing. The term "form of unit dose" refers to physically discrete objects, suitable as a single dose to human subjects and other mammals, each dose contains a defined quantity of active material calculated to produce the desired therapeutic effect, in combination with suitable pharmaceutical excipients. A typical form of single doses include pre-filled, pre-weighed vials or syringes with liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions the compound acetic acid or its derivative is usually smaller component (from about 0.1 to about 50% by Massari preferably from 1 to about 40% by weight), and the rest consists of various solvents or carriers and processing AIDS that help to obtain the desired dosage form.

Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous solvents with buffers, suspendresume and dispersing agents, dyes, perfumes and similar liquids forms, including compositions for injection, described below, and stored in the absence of light to avoid any catalytic action of light, such as the formation of hydroperoxides or peroxides. 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; this excipient as starch or lactose; a spraying agent, such as alginic acid, Primoghel or corn starch; a softening agent such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or a fragrant agent, such as peppermint, methyl salicylate or orange flavoring.

Compositions for injection are usually based on a sterile saline solution for injection, saline solution, phosphate buffer, or other media for injection, known the data in this field. As mentioned above, the derived akriluksusnoy acid of the formula I in such compositions is typically a smaller component, often in the range of between 0.05 and 10% by weight, and the rest is the carrier for injection, etc. Average daily dose will depend on various factors such as the seriousness of the disease and the patient's condition (age, gender and weight). The dose will typically range from 1 mg or more mg to 1500 mg of the compounds of formula (I), optionally divided into several stages. Can also be entered higher doses due to the low toxicity of the compounds of the present invention for extended periods of time.

The above-described components for the compositions of oral administration or by injection are merely explanatory. Additional materials and processing methods, etc. described in part 8 " Remington's Pharmaceutical Sciences Handbook" 18thEdition, 1990, Mack Publishing Company, Easton, Pennsylvania, which is included in this description by reference.

Compounds of the present invention can also be introduced in the form of a slow-release or delivery systems drugs with a slow release. Description of explanatory materials slow release can also be found in the included materials Remington Handbook, as noted above.

This izopet the tion will be explained in the following examples, which should not be construed as limiting the scope of the claims of the invention.

Materials and methods

Synthesis alloxanic acids

Example 1

(3-Benzoyl-2-were)acetic acid

Using as a source of commercially available reagent 2-hydroxybenzophenone and following the experimental technique described in the patent Italy 1283649, synthesize 1-[(2'-hydroxy-3 benzoyl)phenyl]prop-2-EN with a good yield (>75%).

To a cooled (T=-15°C) solution of 1-[(2'-hydroxy-3 benzoyl)phenyl]prop-2-ene (33 mmol) in dry CH2Cl2(70 ml) is added N,N-diisopropylethylamine (59,7 mmol) and the resulting solution was stirred for 30 minutes at T=-15°C. Then the solution is added dropwise to the anhydride triftormetilfullerenov acid (40,16 mmol) and after the introduction of the reagents, the mixture is left to mix for 1 h the Reaction is quenched with 2 N. HCl (100 ml), the two phases are separated and treated; the organic phase is again washed with 2 N. HCl (100 ml), water ( 2 x 100 ml) and saturated NaCl solution (2 x 70 ml), dried Na2SO4and evaporated under reduced pressure to obtain 1-[(2-tripterocalyx-3-benzoyl)phenyl]prop-2-ene (31,3 mmol) as an oily crude substance, pure enough for use in the following stages.

To a solution of 1-[(2-tripterocalyx-3-benzoyl)phenyl]prop-2-EN (30 mmol) in CH2Cl (90 ml) is added water (90 ml), acetic acid (18.2 ml) and Aliquat (1,46 mmol). Parts add KMnO4(103 mmol) for 90 minutes. After the introduction of the reactant mixture is stirred over night. Then added dropwise a 10%solution of sodium metabisulfite until complete discoloration of the solution. The two phases are separated and treated, the organic phase is washed with saturated NaCl solution (2 x 50 ml), dried over Na2SO4and evaporated under reduced pressure to obtain an oily crude substance, which after flash chromatography gives 1-[(2-tripterocalyx-3-benzoyl)phenyl]acetic acid (15 mmol) as a pale yellow oil.

1H NMR (CDCl3): d a 7.85 (m, 2H); to 7.68 (m, 2H); was 7.45 (m, 4H); 3,90 (s, 2H); 2,20 (users, 1H, COOH).

1-[(2-Tripterocalyx-3-benzoyl)phenyl]acetic acid (to 10.3 mmol) is dissolved in methyl alcohol (30 ml) and added to 96% H2SO4(0.2 ml). After stirring over night at room temperature the solution is evaporated under reduced pressure and the residue was diluted with CH2Cl2(50 ml), washed with water (3 x 50 ml), dried over Na2SO4and evaporated under reduced pressure, resulting in a gain methyl ester 1-[(2-tripterocalyx-3-benzoyl)phenyl]acetic acid as a yellow oil (9.2 mmol).

1H-NMR (CDCl3): d 7,80 (m, 2H); the 7.65 (m, 2H); was 7.45 (m, 4H); 3,90 (who, 2H); and 3.72 (s, 3H).

Based on the methyl ester of 1-[(2-tripterocalyx-3-benzoyl)phenyl]acetic acid, get the 2-methyl derivative by reacting the specified triflate with organomanganese according to the methods described T.N. Mitchell, Synthesis, 803, 1992, and K. Ritter, Synthesis, 735, 1993.

Acid synthesized using as the source of the product methyl ester 1-[(2-tripterocalyx-3-benzoyl)phenyl]acetic acid (7.5 mmol)dissolved in dry N-methyl-2-pyrrolidone (25 ml); the mixture of anhydrous LiCl (to 22.5 mmol), triphenylarsine (0.3 mmol) and diallydimethylammonium (0.14 mmol Pd). After 5 minutes at room temperature add tetramethylsilane (8.4 mmol) and the solution stirred for 3 h at T=60°C. After cooling the solution to room temperature the mixture is diluted with n-hexane and add a saturated solution of KF; after filtration and separation of the phases the organic phase is dried over Na2SO4and evaporated under vacuum. After purification of the residue with flash chromatography receive methyl ether (3-benzoyl-2-were)acetic acid. (K. Ritter, Synthesis, 735, 1993, and T.N. Mitchell, Synthesis, 803, 1992).

To a solution of ester type 1 N. NaOH (5 ml) in 1,4-dioxane (5 ml) and the solution stirred at room temperature overnight. After evaporation of the solvent mixture is acidified to pH=2 2 N. HCl until complete precipitation of the product, which kind is collected by filtration as a white solid.

1H-NMR(CDCl3):1H-NMR (CDCl3): d 10,50 (users, 1H, COOH); 7,80 (m, 2H); the 7.65 (m, 2H); was 7.45 (m, 4H); of 3.45 (s, 2H); of 2.25 (s, 3H).

Example 2

(3-Isopropyl-2-were)acetic acid

According to the method described in the patent Italy 1283649, when used as a commercial source of reagent 2'-hydroxyacetophenone, synthesize intermediate connection methyl ester 1-[(2-tripterocalyx-3-isopropyl)phenyl]acetic acid.

1H-NMR (CDCl3): d 7,55-7,40 (m, 3H); 3,85 (s, 2H); 3,70 (s, 3H); of 2.45 (s, 3H).

A solution of methyl ester 1-[(2-tripterocalyx-3-isopropyl)phenyl]acetic acid (7.5 mmol) in dry THF (tetrahydrofuran) (5 ml) slowly dropwise poured to a mixture of methyltriphenylphosphonium (7.5 mmol) and n-BuLi (7.5 mmol; 1.6 M in n-hexane) in dry THF (10 ml). After the introduction of the reagents, the mixture is left under stirring overnight at room temperature. Added dropwise a 10%solution of sodium metabisulfite (20 ml) and the two phases are separated and evaporated; the organic phase is dried over Na2SO4and evaporated under vacuum. After purification of the residue via flash chromatography receive the methyl ester of 1-[(2-tripterocalyx-3-isopropane-2'-yl)phenyl]acetic acid as a colourless oil (5,28 mmol).

1H-NMR (CDCl3): d 7,55-7,40 (m, 3H); of 5.50 (s, 2H); of 3.80 (s, 2H); 3,74 (s, 3H); and 1.63 (s, 3H).

Exercise Voss is the resolution methyl ester 1-[(2-tripterocalyx-3-isopropil-2'-yl)phenyl]acetic acid by hydrolysis over Pd/C in absolute ethanol to obtain, after removal of the catalyst by filtration and evaporating the mother solution under reduced pressure of pure methyl ester (3-isopropyl-2-were)acetic acid as a pale yellow oil (5 mmol).

1H-NMR (CDCl3): d 7,52 was 7.45 (m, 3H); 3,82 (s, 2H); 3,70 (s, 3H); to 2.65 (m, 1H); of 1.25 (d, 6H, J=8 Hz).

Following the method described in example 1, and using as the starting methyl ester (3-isopropyl-2-were)acetic acid (7.0 mmol), synthesized pure (3-isopropyl-2-were)acetic acid (the 5.45 mmol).

1H-NMR (CDCl3): d 11,2 (users, 1H, COOH); 7,35-7,20 (m, 3H); of 3.80 (s, 2H); to 2.55 (m, 1H); 2,22 (s, 3H); of 1.28 (d, 6H, J=8 Hz).

Example 3

(2-Chloro-3-propionitrile)acetic acid

According to the method described in the patent Italy 1283649, and using as a source of commercially available reagent 2'-hydroxypropiophenone, synthesize intermediate 1-[(2-hydroxy-3-propionyl)phenyl]prop-2-ene.

By treating compound PhPCl4according to the method described by Bay et al., J. Org. Chem., Vol.32, 3415, 1990, receive 1-[(2-chloro-3-propionyl)phenyl]prop-2-EN (5.1 mmol). Following the method of oxidation of the double bond, as described in example 1, to synthesize pure (2-chloro-3-propionitrile)acetic acid (4,15 mmol).

1H-NMR (CDCl3): d 10,18 (users, 1H, COOH); 7,40-7,24 (m, 3H); the 3.65 (s, 2H); to 2.75 (q, 2H, J1=8 Hz, J2=3 Hz); to 1.15 (t, 3H, J=8 Hz).

Example 4

(4-Isobutyl-2-were)acetic acid

The connection is obtained by a double reaction of Steele from the source p the agent methyl ester 2-(2-acetoxy-4-performancesthanks)phenylacetic acid (obtained in accordance with known methods) using the same method of experiment that applied for the synthesis of similar arylpropionic acids and is described in WO 01/58852 A2.

1H-NMR (CDCl3): d 7,22 (d, 1H, J=8 Hz); 7,05 (d, 1H, J=8 Hz); 6,92 (s, 1H); 3,50 (s, 2H); 2.40 a (d, 2H, J=7 Hz); of 2.20 (s, 3H); 1,95 (m, 1H); of 0.95 (d, 6H, J=7 Hz).

Example 5

{2-Methyl-4-[(phenylsulfonyl)amino]phenyl}acetic acid

The synthesis of the compounds is as follows.

Commercially available reagent 2-hydroxy-4-nitrobenzoic acid is converted into 2-hydroxy-4-nitroacetophenone on acid chain Melodrama (Meldrum) to methylketones in accordance with the experimental method described Hase T.F. et al., Synthetic Communication, 10(3), 221-224, 1980. Treatment 2-hydroxy-4-nitroacetophenone anhydride triftormetilfullerenov acid gives 2-tripterocalyx derivative, which upon reaction of Steele according to the experimental procedure described in example 1, form 2-methyl-4-nitroacetophenone.

Based on 2-methyl-4-nitrosation, according to the method described in the patent Italy 1283649, synthesize methyl ester of 2-methyl-4-nitrophenylarsonic acid.

1H-NMR (CDCl3): d 7,50-7,42 (m, 3H); of 3.80 (s, 2H); to 3.64 (s, 3H); of 2.25 (s, 3H).

To a solution of methyl ester of 2-methyl-4-nitrophenylarsonic acid (10 mmol) in dry THF (20 ml) and methyl alcohol (20 ml) is added ammonium formate (0.1 mol) and 10% Pd/C (0.5 g) and the resulting mixture is left under stirring for 3 h until complete disappearance of the original is about reagent. The catalyst was removed by filtration and the filtrate is evaporated under vacuum to obtain methyl ester of 2-methyl-4-aminophenylarsonic acid in the form of a waxy substance (which 9.22 mmol).

1H-NMR (CDCl3): d 7,51 (m, 1H); 7,40 (m, 1H); to 7.15 (m, 1H); 5,00 (users, 2H, NH2); is 3.82 (s, 2H); the 3.65 (s, 3H); of 2.20 (s, 3H).

To a solution of methyl ester of 2-methyl-4-amino phenylacetic acid (5.3 mmol) in acetone (10 ml) was added dry pyridine (of 7.95 mmol) and phenylsulfonyl (6,36 mmol) and the resulting solution is stirred over night at room temperature. The acetone is evaporated, and the residue is dissolved CHCl3(15 ml), washed with 1N HCl (2 x 10 ml), water (3 x 20 ml), dried over Na2SO4and evaporated under vacuum, resulting in a gain methyl ether {2-methyl-4-[(phenylsulfonyl)amino]phenyl}acetic acid as a colorless oil (5.0 mmol), pure for use in subsequent reactions. Following the procedure described in example 1, and using as the starting methyl ester (5.0 mmol), synthesized pure {2-methyl-4-[(phenylsulfonyl)amino]phenyl}acetic acid and 4.75 mmol).

1H-NMR (CDCl3): d 9,40 (s, 1H, SO2NH); 7,73 (m, 2H); 7,42 (m, 3H); to 7.50 (m, 1H); 7,45 (m, 1H); to 7.15 (m, 1H); 3,82 (s, 2H); of 2.21 (s, 3H).

According to the same experimental methodology and in the application as a reagent anhydride triftormetilfullerenov acid synthesize the following compounds is the:

Example 6

{2-Methyl-4-[(trifloromethyl)amino]phenyl}acetic acid

1H-NMR (CDCl3): d a 9.35 (s, 1H, SO2NH); rate of 7.54 (m, 1H); 7,40 (m, 1H); 7,20 (m, 1H); of 3.80 (s, 2H); of 2.25 (s, 3H).

Example 7

{2-Chloro-4-[(trifloromethyl)oxy]phenyl}acetic acid

Using as starting compound intermediate 2-hydroxy-4-nitroacetophenone (described in example 5), carry out the synthesis of 2-chlorinated by following the experimental procedure described Bay et al., J.Org. Chem., Vol.32, 3415, 1990. The intermediate 2-chloro-4-nitroacetophenone turn in the intermediate methyl ester 2-chloro-4-aminophenylarsonic acid by the same method that is described in example 5.

1H-NMR (CDCl3): d 7,55 was 7.45 (m, 3H); 3,85 (s, 2H); of 3.60 (s, 3H).

After processing, methyl ester 2-chloro-4-amino phenylacetic acid with sodium nitrite in acidic conditions and following the technique of ion substitution, page hydroxyl group, as described in Organic Synthesis, III, 453, receive (2-chloro-4-hydroxyphenyl)acetic acid as white matter.

1H-NMR (CDCl3): d 7,74-of 7.60 (m, 3H); 6,35 (users, 1H, OH); 3,85 (s, 2H).

A mixture of the above (2-chloro-4-hydroxyphenyl)acetic acid (2 mmol), anhydride triftormetilfullerenov acid (4 mmol) in dry pyridine (1 ml) is heated at T=60°C for 24 hours. After cooling to room temperature the reaction mixture is poured into 1 N. HCl (5 is l) and the aqueous solution extracted with CH 2Cl2(3 x 10 ml). The collected organic extracts are washed with 1 N. NaOH (2 x 10ml), dried over Na2SO4and evaporated under reduced pressure, resulting in a gain of crude residue. As a result of crystallization in isopropyl ether wet substances get clean {2-chloro-4-[(trifloromethyl)oxy]phenyl}acetic acid as a white solid (1, 25 mmol).

1H-NMR (CDCl3): 7,70 d to 7.62 (m, 3H); 3,85 (s, 2H).

Example 8

(5-Benzoyl-1-methyl-1H-pyrrol-2-yl)acetic acid

The compound is synthesized using as starting compounds commercial reagents 1-methyl-2-paracervical and benzoyl chloride following the experimental procedure described in Di Santo R. Et al. Synth. Comm., 25(6), 787-793 (1995).

1H-NMR (CDCl3): d a 7.85 (m, 2H); 7,52 (m, 1H); was 7.45 (m, 2H); 6,70 (s, 1H); x 6.15 (s, 1H); of 3.97 (s, 3H); 3.75 to (s, 2H); 3,0 (users, 1H, COOH).

According to the same experimental procedure and utilizing as starting compounds related commercial acylchlorides receive the following connections:

Example 9

[1-Methyl-5-(4-chlorobenzoyl)-1H-pyrrol-2-yl]acetic acid

1H-NMR (CDCl3): d of 7.82 (d, 2H, J=8 Hz); 7,58 (d, 2H, J=8 Hz); 7,20 (s, 1H); of 6.68 (s, 1H); of 3.75 (s, 2H); 3,70 (s, 3H).

Example 10

[1-Methyl-5-[(4-methylbenzoyl)-1H-pyrrol-2-yl]acetic acid

1H-NMR (CDCl3): d 7,80 (d, 2H, J=8 Hz); at 7.55 (d, 2H, J=8 Hz); 7.18 in (s, 1H); 6,72 (s, 1H); of 3.75 (s, 2H); 3,70 (s, 3H); 2,35, 3H).

Example 11

(5-Acetyl-1-methyl-1H-pyrrol-2-yl)acetic acid

1H-NMR (CDCl3): d of 6.90 (d, 1H, J=3 Hz); 6,05 (d, 1H, J=3 Hz); of 3.80 (s, 3H); 3,62 (s, 2H); 2,32 (s, 3H).

Example 12

(5-Isobutyryl-1-methyl-1H-pyrrol-2-yl)acetic acid

1H-NMR (CDCl3): d of 7.55 (s, 1H); 6,32 (s, 1H); the 3.65 (s, 2H); to 3.52 (s, 3H); 3.15 in (m, 1H); of 1.05 (d, 6H, J=7 Hz).

Example 13

(1-Benzoyl-2-methyl-1H-pyrrol-3-yl)acetic acid

The intermediate ethyl ester (2-methyl-1H-pyrrol-3-yl)acetic acid was synthesized as described Bertschy, H., et al., Angew. Chem. Int. Ed. Engl. 29(7), 777-778(1990).

Subsequent N-benzoylation and hydrolysis of ester is well known methods (NaH/benzoyl chloride) to give the desired product.

1H-NMR (CDCl3): d 8,15 (m, 2H); 7,60 (m, 1H); was 7.45 (m, 2H); to 6.95 (d, 1H, J=3 Hz); 6,32 (d, 1H, J=3 Hz); 4,50 (users, 1H, COOH); 3,85 (s, 2H); to 2.35 (s, 3H).

Example 14

(1-Benzoyl-2-chloro-1H-pyrrol-3-yl)acetic acid

The product is obtained by a multi-stage synthesis according to well known literature methods. Condensation commercial reagent diethylmalonate in the presence of dimethylacetal of bromoacetaldehyde and hydrolysis of the acetal allow to obtain the intermediate aldehyde, which after treatment with gaseous ammonia and dehydration are not selected intermediate enamine give pure intermediate ethyl ester 2-hydroxyprop-3-acetic acid.

1H-NMR (CDCl3): d 10,35 (users, 1H, NH);7,21 (d, 1H, J=3 Hz); 7,05 (users, 1H, OH); 6,35 (d, 1H, J=3 Hz); of 4.12 (q, 2H, J=7 Hz); of 3.45 (s, 2H); to 1.31 (t, 3H, J=7 Hz).

Intermediate pyrrol after processing PCl5gives 2-chlorinated, which after hydrolysis of ester under normal conditions (NaOH/CH2OH) and N-benzoylation forms a pure compound (1-benzoyl-2-chloro-1H-pyrrol-3-yl)acetic acid as a white solid (yield 78%).

1H-NMR (DMSO-d6): d 8,15 (m, 2H); 7,60 (m, 1H); was 7.45 (m, 2H); 6,92 (d, 1H, J=3 Hz); 6,35 (d, 1H, J=3 Hz); 4,65 (users, 1H, COOH); is 3.82 (s, 2H).

Example 15

(1-Benzoyl-2-methyl-1H-indol-3-yl)acetic acid

Commercially available reagent 2-methyl-3-introcaso acid (3 mmol) is treated with NaH (6.6 mmol) and benzoyl chloride (6.6 mmol) in dry THF (10 ml) well-known methods. The usual reaction mixture is processed and the residue is crystallized in a simple isopropyl ether to obtain pure (1-benzoyl-2-methyl-1H-indol-3-yl)acetic acid as a white solid (2.25 mmol).

1H-NMR (CDCl3): d 7,82-of 7.70 (m, 3H); at 7.55 (t, 2H, J=8.5 Hz); 6.90 to-to 6.80 (m, 2H); of 6.65 (m, 2H); 3,62 (s, 2H); 3,30 (s, 3H).

Example 16

[1-(4-Chlorobenzoyl)-2-methyl-1H-indol-3-yl]acetic acid

Commercially available reagent 2-methyl-3-introcaso acid (3 mmol) is treated with NaH (6.6 mmol) and 4-chlorobenzylchloride (6.6 mmol) in dry THF (10 ml) well-known methods. The usual reaction mixture is processed and the OST is the current crystallized in a simple isopropyl ether to obtain pure [1-(4-chlorobenzoyl)-2-methyl-1H-indol-3-yl]acetic acid as a white solid (for 2.01 mmol).

1H-NMR (CDCl3): d 7,80-of 7.70 (t, 2H, J=8.5 Hz); at 7.55 (t, 2H, J=8.5 Hz); 6.90 to (s, 1H); to 6.80 (m, 1H); of 3.60 (s, 2H); 3,30 (s, 3H).

Example 17

(1-Isopropyl-2-methyl-1H-pyrrol[2,3-b]pyridine-3-yl)acetic acid

Commercially available reagent 1H-pyrrol[2,3-b]pyridine (3 mmol) is treated with NaH (3.3 mmol) and isopropylchloride (3.3 mol) in dry THF (10 ml) well-known methods. The usual reaction mixture is processed and the residue purified chromatographically to obtain pure 1-isopropyl-1H-pyrrol[2,3-b]pyridine as a white solid (and 2.83 mmol).

1H-NMR (CDCl3): d the 7.65 (m, 1H); 7,15-was 7.08 (m, 2H); 7,00 (m, 1H); 6,50 (m, 1H); of 3.12 (m, 1H); of 1.05 (d, 6H, J=7 Hz).

Following the experimental procedure described Chi S. M. et al., Tetrahedron Letters, 41, 919-922 (2000) and using as starting compound 1-isopropyl-1H-pyrrol[2,3-b]pyridine (2.5 mmol), allocate (1-isopropyl-2-methyl-1H-pyrrol[2,3-b]pyridine-3-yl)ethoxyacetic (2.0 mmol). The final oxidation KMnO4in terms of catalysis treatment phases (described in example 1) leads to the formation of the desired product (1-isopropyl-2-methyl-1H-pyrrol[2,3-b]pyridine-3-yl)acetic acid (of 1.85 mmol).

1H-NMR (CDCl3): d to 7.15 (m, 1H); 7,10 (m, 1H); to 6.95 (m, 1H); 3,55 (s, 2H); 3,11 (m, 1H); to 2.35 (s, 3H); of 1.05 (d, 6H, J=7 Hz).

Example 18

(3-Benzoyl-2-methoxyphenyl)acetic acid

Methyl ether (3-benzoyl-2-hydroxyphenyl)acetic acid obtained according to known methods from 2-d is dioxibenzene, treated with potassium carbonate and iodomethane in acetone to obtain the corresponding 2-methoxypropanol, which after the usual hydrolysis (NaOH/CH3OH) gives (3-benzoyl-2-methoxyphenyl)acetic acid as a white solid.

1H-NMR (CDCl3): d of 7.90 (d, 2H, J=7 Hz); a 7.62 (m, 1H); 7,50-7,40 (m, 3H); 7,35 (m, 1H); to 7.15 (t, 1H, J=7 Hz); 3,82 (s, 2H); of 3.60 (s, 3H)

Synthesis of amides akriluksusnoy acid

In accordance with the experimental method described in WO 01/58852, and using as starting reagent related acetic acid, synthesize the following compounds:

Example 19

(5-Acetyl-1-methyl-1H-pyrrol-2-yl)ndimethylacetamide

1H-NMR (CDCl3): d 6,92 (d, 1H, J=3 Hz); 6,05 (d, 1H, J=3 Hz); 5.25-inch (users, 2H, CONH2); 3,81 (s, 3H); 3,68 (s, 2H); to 2.35 (s, 3H).

Example 20

(5-Acetyl-1-methyl-1H-pyrrol-2-yl)-N-carboxymethylated

1H-NMR (CDCl3): d of 6.90 (d, 1H, J=3 Hz); 6,05 (d, 1H, J=3 Hz); 5,95 (d, 1H, J=7 Hz, CONH); of 4.05 (d, 2H, J=7 Hz); 3,81 (s, 3H); 3,68 (s, 2H); to 2.35 (s, 3H).

Example 21

(S)(5-Acetyl-1-methyl-1H-pyrrol-2-yl)-N-(2-carboxyethyl)ndimethylacetamide

1H-NMR (CDCl3): d 6,92 (d, 1H, J=3 Hz); 6,05 (d, 1H, J=3 Hz); 6,00 (users, 1H, CONH); a 4.53 (q, 1H, J=7 Hz); 3,81 (s, 3H); 3,68 (s, 2H); to 2.35 (s, 3H); of 1.55 (d, 3H, J=7 Hz).

Example 22

(5-Acetyl-1-methyl-1H-pyrrol-2-yl)-N-(3-dimethylaminopropyl) ndimethylacetamide

1H-NMR (CDCl3): d 7,75 (users, 1H, CONH); 6,92 (d, 1H, J=3 Hz); 6,28 (d, 1H, J=3 Hz); 4,10 (s, 3H); of 3.80 (s, 2H); of 3.54 (m, 2H); 2,48 (t, 2H, J=7 Hz; is 2.40 (s, 3H); 2,19 (s, 6H); to 1.76 (m, 2H).

Example 23

(S)(5-Acetyl-1-methyl-1H-pyrrol-2-yl)-N-(1-carboxy-2-methoxyethyl)ndimethylacetamide

1H-NMR (CDCl3): d 7,45 (users, 1H, CONH); 6,92 (d, 1H, J=3 Hz); 6,05 (d, 1H, J=3 Hz); a 4.53 (q, 1H, J=7 Hz); 3,81 (s, 3H); 3,68 (s, 2H); 3,20 (s, 3H); 3.15 in (d, 2H, J=7 Hz); 2,35 (s, 3H).

Example 24

(4-Isobutyl-2-were)ndimethylacetamide

1H-NMR (CDCl3): 7,20 d (d, 1H, J=8 Hz); 7,05 (d, 1H, J=8 Hz); 6,95 (s, 1H); 5,70 (users, 2H, CONH2); 3,68 (s, 2H); 2.40 a (d, 2H, J=7 Hz); 2,22 (s, 3H); 1,95 (m, 1H); of 0.95 (d, 6H, J=7 Hz).

Example 25

(2-Chloro-3-propionitrile)-N-(3-dimethylaminoethyl)ndimethylacetamide

1H-NMR (CDCl3): d 7,50 (users, 1H, CONH); 7,40-7,24 (m, 3H); 3,62 (s, 2H); of 3.54 (m, 2H); to 2.75 (q, 2H, J1=8 Hz, J2=3 Hz); of 2.25 (t, 2H, J=7 Hz); 2,19 (s, 6H); to 1.15 (t, 3H, J=8 Hz).

Example 26

(3-Isopropyl-2-were)-N-[3-(1-piperidinyl)propyl]ndimethylacetamide

1H-NMR (CDCl3): d 7,45 (users, 1H, CONH); 7,35-7,20 (m, 3H); of 3.80 (s, 2H); 3,50 (m, 2H); of 3.32 (m, 2H); 2.95 and (m, 2H); to 2.55 (m, 1H); of 2.45 (m, 2H); 2,22 (s, 3H); 2,10 (m, 2H); 1,90 (m, 6H); of 1.28 (d, 6H, J=8 Hz).

Example 27

(3-Benzoyl-2-were)ndimethylacetamide

1H-NMR (CDCl3): d of 7.82 (m, 2H); of 7.60 (m, 2H); was 7.45 (m, 4H); 5,45 (users, 2H, CONH2); 3,70 (s, 2H); of 2.25 (s, 3H).

Example 28

(1-Benzoyl-2-methyl-1H-indol-3-yl)ndimethylacetamide

1H-NMR (CDCl3): d 7,82-of 7.70 (m, 3H); at 7.55 (t, 2H, J=8.5 Hz); 6.90 to-to 6.80 (m, 2H); of 6.65 (m, 2H); 5,75 (users, 2H, CONH2); 3,68 (s, 2H); 3,30 (s, 3H).

Example 29

(1-Benzoyl-2-methyl-1H-indol-3-yl)-N-(3-dimethylaminopropyl)ndimethylacetamide

1H-I Is R (CDCl 3): d 7,80-7,72 (m, 3H); 7,60 (users, 1H, CONH); at 7.55 (t, 2H, J=8.5 Hz); 6.90 to-to 6.80 (d, 2H, J=8 Hz); of 6.65 (d, 2H, J=8 Hz); of 3.80 (s, 2H); to 3.58 (m, 2H); 3,30 (s, 3H); 2.50 each (t, 2H, J=7 Hz); of 2.20 (s, 6H); of 1.80 (m, 2H).

Example 30

[1-(4-Chlorobenzoyl)-2-methyl-1H-indol-3-yl]ndimethylacetamide

1H-NMR (CDCl3): d 7,80-of 7.70 (m, 2H, J=8.5 Hz); at 7.55 (t, 2H, J=8.5 Hz); 6,92-to 6.80 (d, 2H, J=8 Hz); of 6.68 (d, 2H, J=8 Hz); 5,62 (users, 2H, CONH2); 3,70 (s, 2H); 3,30 (s, 3H).

Example 31

[1-(4-Chlorbenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]ndimethylacetamide

1H-NMR (CDCl3): d 7,82 to 7.75 (m, 2H, J=8.5 Hz); at 7.55 (m, 2H); 6,92-6,70 (m, 3H); ceiling of 5.60 (users, 2H, CONH2); is 3.82 (s, 3H); 3,66 (s, 2H); 3,30 (s, 3H).

Example 32

{2-Chloro-(trifloromethyl)oxy]phenyl}-N-(2-hydroxyethoxyethyl)ndimethylacetamide

1H-NMR(CDCl3): 7,70 d to 7.62 (m, 3H); 5,90 (users, 1H, CONH); of 3.80 (s, 2H); the 3.65 (m, 2H); 3,55-of 3.32 (m, 6H); 2,05 (users, 1H, OH).

Example 33

(1-Benzoyl-2-methyl-1H-pyrrol-3-yl)-N-(2-methoxyethyl)ndimethylacetamide

1H-NMR (CDCl3): d to 8.12 (m, 2H); 7,60 (m, 1H); to 7.50 (m, 2H); 6,92 (d, 1H, J=3 Hz); 6,32 (d, 1H, J=3 Hz); 5,65 (user,s, 1H, CONH); of 3.75 (s, 2H); of 3.25 (t, 2H, J=8 Hz); 3,20 (s, 3H); of 2.97 (m, 2H); to 2.35 (s, 3H).

Example 34

(1-Benzoyl-2-chloro-1H-pyrrol-3-yl)-N-[3-(1-morpholino)propyl]ndimethylacetamide

1H-NMR (CDCl3): d 8,15 (m, 2H); 7,60 (m, 1H); was 7.45 (m, 2H); 6,92 (d, 1H, J=3 Hz); 6,35 (d, 1H, J=3 Hz); 6,20 (user,s, 1H, CONH); of 3.78 (s, 2H); of 3.25 (m, 4H); 2,98 (m, 2H); of 2.45 (m, 6H); of 1.80 (m, 2H).

Example 35

(5-Isobutyryl-1-methyl-1H-pyrrol-2-yl)ndimethylacetamide

1H-NMR (CDCl3): d to 7.50 (s, 1H); 6,35 (s, 1H); 5,85 (user,s, 2H, CONH2) of 3.77 (s, 2H); 3,50 (s, 3H); 3,18 (m, 1H); of 1.05 (d, 6H, J=7 Hz).

Example 36

(5-Benzoyl-1-methyl-1H-pyrrol-2-yl)-N-(2-carboxymethyl)ndimethylacetamide

1H-NMR (CDCl3): d 10,53 (user,s, 1H, COOH), a 7.85 (m, 2H); 7,52 (m, 1H); was 7.45 (m, 2H); 6,70 (s, 1H); x 6.15 (s, 1H); 5,95 (d, 1H, J=7 Hz, CONH); of 4.05 (d, 2H, J=7 Hz) of 3.95 (s, 3H); 3,68 (s, 2H).

Example 37

[1-Methyl-5-(4-chlorobenzoyl)-1H-pyrrol-2-yl]-N-(2-hydroxyethoxyethyl)ndimethylacetamide

1H-NMR (CDCl3): d of 7.82 (d, 2H, J=8 Hz); at 7.55 (d, 2H, J=8 Hz); 7,40 (user,s, 1H, CONH); to 7.35 (s, 1H); of 6.65 (s, 1H); 3,70 (s, 2H); the 3.65 (s, 3H); of 3.60 (m, 2H); 3,50-of 3.42 (m, 6H); 2,25 (user,s, 1H, OH).

Example 38

[1-Methyl-5-(4-chlorobenzoyl)-1H-pyrrol-2-yl]ndimethylacetamide

1H-NMR (CDCl3): d of 7.82 (d, 2H, J=8 Hz); 7,58 (d, 2H, J=8 Hz); 7,20 (s, 1H); of 6.68 (s, 1H); 6,35 (user,s, 2H, CONH2); 3,70 (s, 3H); 3,66 (s, 2H).

Example 39

{2-Methyl-4-[(phenylsulfonyl)amino]phenyl}-N-(3-dimethylaminopropyl)ndimethylacetamide

1H-NMR (CDCl3): d 9,20 (s, 1H, CO2NH); to 7.75 (m, 2H); 7,65 (user,s, 1H, CONH); 7,42 (m, 3H); to 7.50 (m, 1H); 7,45 (m, 1H); for 7.12 (m, 1H); 3,88 (s, 2H); to 3.58 (m, 2H); 2.50 each (t, 2H, J=7 Hz); 2,35 (s, 6H); of 2.21 (s, 3H); of 1.80 (m, 2H).

Example 40

(3-Benzoyl-2-methoxyphenyl)ndimethylacetamide

1H-NMR (CDCl3): d of 7.90 (d, 2H, J=7 Hz); a 7.62 (m, 1H); 7,50-7,40 (m, 3H); 7,35 (m, 1H); to 7.15 (t, 1H, J=7 Hz); 6,55 (user,s, 2H, CONH2); is 3.82 (s, 3H); 3,66 (s, 2H).

Synthesis of methanesulfonamido akriluksusnoy acid

According to the experimental procedure described in WO 00/24710, and based on related acetic acid, synthesize the following compounds:

Por what measures 41

(5-Acetyl-1-methyl-1H-pyrrol-2-yl)acetylethanolamine

1H-NMR (CDCl3): d 7,50 (user,s, 1H, CONH); make 6.90 (d, 1H, J=3 Hz); 6,05 (d, 1H, J=3 Hz); of 3.80 (s, 3H); to 3.58 (s, 2H); up 3.22 (s, 3H); 2,32 (s, 3H).

Example 42

(4-Isobutyl-2-were)acetylethanolamine

1H-NMR (CDCl3): 7,20 d (d, 1H, J=8 Hz); 7,10 (user,s, 1H, CONH); 7,00 (d, 1H, J=8 Hz); 6,85 (s, 1H); the 3.65 (s, 2H); up 3.22 (s, 3H); 2.40 a (d, 2H, J=7 Hz); 2,22 (s, 3H); 1,95 (m, 1H); of 0.95 (d, 6H, J=7 Hz).

Example 43

{2-Methyl-4-[(trifloromethyl)amino]phenyl} acetylethanolamine

1H-NMR (CDCl3): d 9,42 (user,s, 1H, CO2NH); 7,45 (user,s, 1H, CONH); 7,52 (m, 1H); 7,45 (m, 1H); 7,20 (m, 1H); 3,85 (s, 2H); of 3.45 (s, 3H); of 2.25 (s, 3H).

Example 44

[1-Methyl-5-[(4-methylbenzoyl)-1H-pyrrol-2-yl]acetylethanolamine

1H-NMR (CDCl3): d 7,80 (d, 2H, J=8 Hz); at 7.55 (d, 2H, J=8 Hz); 7,38 (user,s, 1H, CONH); to 7.18 (s, 1H); 6,72 (s, 1H); 3,82 (s, 2H); 3,70 (s, 3H); 3.42 points (s, 3H); to 2.35 (s, 3H).

Table II presents the chemical names and structural formulas of the compounds of examples 1-44.

1. The use of compounds 2-akriluksusnoy acid and amides of formula (I):

and their pharmaceutically acceptable salts,
where a includes the atom, X represents a phenyl or 5-6-membered
heteroaromatic ring, optional content is suitable heteroatom, selected from N;
figures 1 and 2 marked with the relevant provisions of the ring A;
atom X is selected from N (nitrogen) and C (carbon);
R means the replacement group on the ring And selected from:
group 3 (meta) position selected from the group comprising straight or branched C1-C5-alkyl, C2-C5-acyl;
group in the 4 (para) position selected from the group comprising C1-C5- alkyl, C1-C5-alkanesulfonyl substituted by halogen;
Hy represents a small hydrophobic group with a value of the coefficient of steric difficulties ν in the interval between 0.5 and 0.9
(where ν is the steric constant Carton (Charton steric constant) for alternates), including methyl, ethyl, chlorine, bromine,
the group Y is selected from O (oxygen) and NH;
when Y represents O (oxygen), R' represents H (hydrogen);
when Y represents NH, R' is selected from the group:
N
residue of the formula SO2Rd, where Rd denotes C1-C6-alkyl,
upon receipt of a medicinal product, which is the inhibitor-induced IL-8 of PMN chemotaxis (CXCR1) or induced GRO-α of PMN chemotaxis (CXCR2).

2. The use according to claim 1, where a represents phenyl, pyridine, pyrrole, pyrimidine, imidazole.

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

4. The use according to claim 1, where Y represents NH, and R' is a residue of the formula SO2Rd, where Rd denotes methyl, those who or isopropyl.

5. The use according to any one of claims 1 to 4, where R is 3'-acetyl, 3'-propionyl, 3'-Isobutanol, 3'-ethyl, 3'-isopropyl, 4'-isobutyl, 4'-triftormetilfullerenov.

6. The use according to any one of claims 1 to 4, where Nu is selected from methyl, ethyl, chlorine, bromine.

7. The use according to claim 1, where the compound is selected from the following:
(3-isopropyl-2-were)acetic acid,
(4-isobutyl-2-were)acetic acid,
{2-methyl-4-[(trifloromethyl)amino]phenyl}acetic acid,
(5-acetyl-1-methyl-1H-pyrrol-2-yl)acetic acid,
(5-isobutyryl-1-methyl-1H-pyrrol-2-yl)acetic acid,
(5-acetyl-1-methyl-1H-pyrrol-2-yl)acetamide", she
(4-isobutyl-2-were)ndimethylacetamide,
(5-isobutyryl-1-methyl-1H-pyrrol-2-yl)ndimethylacetamide.

8. The use according to claims 1 to 4 or 7 when getting medicines 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 disorders caused by ischemia and reperfusion.

9. The sulfonamides of the formula (1A)

and their pharmaceutically acceptable salts;
where a includes the atom, X represents a phenyl or 5-6-membered heteroaromatic ring, optionally including a heteroatom selected from N;
figures 1 and 2 marked with the appropriate state is on ring A; atom X is selected from N (nitrogen) and C (carbon);
R means the replacement group on the ring And selected from:
group 3 (meta) position selected from the group:2-C5-acyl, benzoyl, substituted stands;
group in the 4 (para) position selected from the group:1-C5-alkyl, C1-C5-alkanesulfonyl, substituted with halogen,
Hy represents a small hydrophobic group with a value of the coefficient of steric difficulties ν in the interval between 0.5 and 0.9
(where ν is the steric constant Carton (Charton) for alternates), including methyl, ethyl,
Rd means C1-C6-alkyl.

10. Compounds according to claim 9,
where a represents a benzene, pyridine, pyrimidine, pyrrole, imidazole,
Rd represents a methyl, ethyl or isopropyl;
Hy is selected from methyl, ethyl.

11. Compounds according to claim 9, selected from
(5-acetyl-1-methyl-1H-pyrrol-2-yl)acetyl methanesulfonamide,
(4-isobutyl-2-were)acetyl methanesulfonamide,
{2-methyl-4[(trifloromethyl)amino]phenyl}acetylethanolamine,
[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetylethanolamine.

12. Compounds according to any one of p-11 for use as medicinal products that are inhibitors induced IL-8 of PMN chemotaxis (CXCR1) or induced GRO-α of PMN chemotaxis (CXCR2).

13. Connection 12 for use in the treatment of SS is riaza, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous of pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of disorders caused by ischemia and reperfusion.

14. Pharmaceutical composition, which is the inhibitor-induced IL-8 of PMN chemotaxis (CXCR1) or induced GRO-α of PMN chemotaxis (CXCR2), including a pharmaceutically effective amount of 2-akriluksusnoy acid and amides of formula (I):

and their pharmaceutically acceptable salts,
where a includes the atom, X represents a phenyl or 5-6-membered heteroaromatic ring, optionally containing a heteroatom selected from N;
figures 1 and 2 marked with the relevant provisions of the ring A;
atom X is selected from N (nitrogen) and C (carbon);
R means the replacement group on the ring And selected from:
group 3 (meta) position selected from the group comprising straight or branched C1-C5-alkyl, C2-C5-acyl;
group in the 4 (para) position selected from the group comprising From1-C5-alkyl, C1-C5-alkanesulfonyl substituted by halogen;
Hy represents a small hydrophobic group with a value of the coefficient of steric difficulties ν in the interval between 0.5 and 0.9
(where ν is starecheski the th constant Carton (Charton steric constant for substituents), includes methyl, ethyl, chlorine, bromine,
the group Y is selected from O (oxygen) and NH;
when Y represents O (oxygen), R' represents H (hydrogen);
when Y represents NH, R' is selected from the group:
N
residue of the formula SO2Rd, where Rd denotes C1-C6-alkyl,
or compounds according to claim 9 as an active ingredient in a mixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention refers to new spirocyclic cyclohexane derivatives of general formula I , where: R1-R3, R5-R10, W, X are disclosed in the claim 1 of formula.

EFFECT: compounds exhibit analgesic activity to be applied for making a medical product for pain therapy.

20 cl, 1 tbl, 54 ex

FIELD: chemistry.

SUBSTANCE: described are 2,4,6-phenyl-substituted cyclic ketoenols of formula (I, in which W, X, Y and CKE are given in invention formula. Also described are esters of acylamino acids of formula (II), substituted derivatives of phenylacetic acid of formula (XXIX), (XXVII), (XXXI), which are intermediate compounds for obtaining formula (I) compound.

EFFECT: obtaining herbicidal preparation containing combinations of biologically active substances, including (a), formula (I) compound and (b') improving compatibility with cultural plants mefenpyr-diethyl, with weight ratio 5-1:1-7.7.

9 cl, 46 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: described is compound of general formula , in which W and Z represent N, and X and Y represent CH; R represents halogen; R1 represents phenyl, substituted with 1-3 substituents, selected from halogen; R2 represents NR3R4; R3 and R4 independently represent H, C1-C8alkyl, C2-C8alkenyl, halogen(C1-C8)alkyl, C1-C4alkoxy(C1-C8)alkyl, C3-C8cycloalkyl, optionally substituted with methyl, or R3 and R4 together form C3-C7alkylene chain, optionally containing as substituent C1-C4alkyl group, or together with nitrogen atom, to which they are bound, R3 and R4 form morpholine or pyperazine-N-(C1-C4)alkyl (more preferably N-methyl) ring. Described is method of obtaining compound of general formula (I), intermediate chemical products, as well as fungicidal composition for plants and method to combat phytopathogenic fungi or their elimination, using compound of formula (I).

EFFECT: increase of compound fungicidal activity.

10 cl, 133 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: described is novel compound of formula (I)

or its pharmaceutically acceptable salt, values of radicals are given in invention formula Compound has ability to inhibit receptor mGluR5, which intends it for prevention and/or treatment of receptor mGluR5- associated disturbances. Also described is pharmaceutical composition, method of inhibiting activation of receptors mGluR5, using compound of formula (I). Described is method of obtaining compound of formula 1a or 1b structure.

EFFECT: increasing output of suitable product.

18 cl, 825 ex

FIELD: chemistry.

SUBSTANCE: invention refers to imidazoquinolines of formula (I) and (II) , as well as to tetrahydroimidazoquinolines of formula (III) wherein radicals and symbols possess values specified in formula of the invention. The given compounds and based pharmaceutical compositions representing subject of the present invention, can stimulate biosynthesis of various cytokines, particularly, α-interferon and are used in treating certain diseases, including virus diseases and cancerous diseases.

EFFECT: objects of invention are also methods of treating virus and cancerous diseases and intermediate compounds.

41 cl, 2 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to tetrahydroquinoline derivatives, described by formula (I) where t is equal to 0, 1 or 2; each R independently represents H, alkyl, alkenyl, alkinyl, halogenalkyl, cycloalkyl; n is equal to 0; R2 is chosen from the group consisting of H, alkyl, halogenalkyl, cycloalkyl, -Racycloalkyl, alkenyl, alkinyl, -RaAy, -RaOR5; where R2 is not substituted with amine or alkylamine; R3 represents H; each R4 independently represents halogen, halogenalkyl, alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkenyl, -A'y, -NHAy, -Het, -NHHet, -OR10, -NR6R7, -RaNR6R7, -C(O)NR6R7, -C(O)Ay, -C(O)Het; m is equal to 0, 1 or 2; each R5 independently represents H; p is equal to 0 or 1; Y represents NR10-, -O-, -C(O)NR10-, -NR10C(O)-, -C(O)- , - -NR10C(O)N(R10)-; X represents -N(R10)2, -RaN(R10)2, -AyN(R10)2, -RaAyN(R10)2, -AyRaN(R10)2, -RaAyRaN(R10)2, -Het, -RaHet, -HetN(R10)2, -RaHetN(R10)2, -HetRaN(R10)2, - RaHetRaN(R10)2; each Ra independently represents alkylen, optionally substituted with with one or more alkyl; each R10 independently represents H, alkyl, cycloalkyl, alkenyl, alkinyl, cycloalkenyl, -Racycloalkyl; each R6 and R7 is independently chosen from H, alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkenyl, -Racycloalkyl, -RaNR8R9; each R8 and R9 is independently chosen from H or alkyl; each Ay independently represents optionally substituted aryl group; and each Het independently represents optionally substituted 4-, 5- or 6-merous heterocyclil or heteroaryl group where heteroatoms are chosen from N and O; or its pharmaceutically acceptable salt, or ester. Besides, there are disclosed pharmaceutical composition based on compound of formula (I), its application and methods of production.

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53 cl, 2 tbl, 105 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: there are disclosed compounds composed as to formula , where n and m stand for integer 1 to 3; z stands for integer 0 to 1; R is chosen from hydrogen, hydroxy or alkoxy; R2 stands for hydrogen; R3 and R4 are independently chosen from the group consisting of hydrogen, halogen; R5 is chosen from the group consisting of halogen, alkyl; R6 represents alkyl; E is chosen from the group specified in item 1 of formula of invention, A is chosen from N and C(R11), X is chosen from C, a stands for double bond and b stands for single bond; and Y is chosen from N(R1) provided when Y stands for N(R1), X stands for C, where R1 is chosen from C3-C6-cyclolkyl, phenyl; provided if A stands for C(R11), X stands for C, and Y stands for N(R1), then R11 and R1 can be bonded thus forming morpholinyl.

EFFECT: compounds possess antibacterial activity and are suitable as antibacterial means for treating bacterial infections in humans and animals.

13 cl, 10 tbl

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new 7-azaindoles with general formula 1: where (a) A stands for an N-oxide group and B stands for CH, nitrogen, (b) A stands for nitrogen and B stands for an N-oxide group, or (c) A and B stand for an N-oxide group, R1 stands for (i) -C1-10-alkyl, unbranched or branched, which, if necessary, is monosubstituted with saturated mono- C3-C6carbocycle, or mono-, bi- multi-unsaturated C6-C10carbocycle. C6-10-aryl groups in turn, if necessary, can be mono- or multi-substituted with -C1-6-alkyl, -CN, -F, -CI, -Br, -I, -O-C1-6-alkyl groups. Alkyl groups in carboxylic substitutes, in turn, if necessary, can be mono- or multi-substituted with -F groups. R2 stands for hydrogen, C1-C3alkyl. R3 and R4 are identical or different, and stand for hydrogen, -F, -Cl, -Br, -I. The invention also relates to pharmaceutical salts of these 7-azaindoles.

EFFECT: compounds with general formula I exhibit phosphodiesterase 4 inhibiting activity, which allows for their use as therapeutic active substances for making medicinal agents, which suppress pulmonary neutrophilia and eosinophilia.

14 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to hexahydropyrido[1,2-a]pyrazine derivatives. The invention also relates to methods of producing these compounds, to pharmaceutical compositions, containing a pharmacologically active amount of at least, one of these compounds as an active ingredient, as well as to use of these compositions for treating disorders, involving neurokinin receptors. The invention also relates to compounds with general formula (1) in which the denotations of symbols are given in the description.

EFFECT: exhibition of antagonistic activity towards neurokinin receptor NK1.

6 cl, 13 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with general formula (I), in which X1 is phenyl, 9-member bicyclic heteroaryl, containing S or O as heteroatoms, or 5-member heteroaryl, containing S or O as heteroatoms, each of which is optionally substituted with one or more substitutes, chosen from halogen or C1-6alkyl, which is optionally substituted with one or more halogens. X2 is phenyl, which is optionally substituted with one or more substitutes, chosen from halogen, or 5-member heteroaryl, containing S or O as heteroatoms. Ar is phenylene, which is optionally substituted with one or more substitutes, chosen from halogen, or C1-6alkyl, phenyl, C1-6alkoxy, each of which is optionally substituted with one or more halogens. Y1 is O or S, and Y2 represents O, Z represents -(CH2)n-, where n equals 1, 2 or 3. R1 is hydrogen or C1-6alkoxy and R2 is hydrogen, C1-6alkyl. The invention also relates to pharmaceutical salts of these compounds or any of their tautomeric forms, stereoisomers, stereoisomer mixtures, including racemic mixtures.

EFFECT: invention also pertains to use of these compounds as pharmaceutical compositions, with effect on receptors, activated by the peroxisome proliferator PPARδ subtype, and to pharmaceutical compositions, containing these compounds (I).

36 cl, 41 ex

Dpp-iv inhibitors // 2345067

FIELD: chemistry, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of general formula (I) Z-C(R1R2)-C(R3NH2)-C(R4R5)-X-N(R6R7) (I), or its pharmaceutically acceptable salt which is different because Z represents phenyl; where Z can be substituted with one or more R8, where R8 represents halogen; R1, R4 represent H; R2, R5 represent H; R3 represents H; X is selected from group consisting of S(O)2 and C(O); R6, R7 are independently selected from group consisting of H, (C(R29R30))m-X1-Z1 and (C(R31R32))n-X2-X3-Z2 and C1-4alkyl, which carries substitution with one or more R29a, where R29a is independently selected from group consisting of R29b and Z1, on condition that R6 and R7 are selected in such way that R6 and R7 were not simultaneously independently selected from group consisting of H, CH3, CH2CH3, CH2CH2CH3 and CH(CH3)2; R29 R29b, R30, R31, R32 are independently selected from group consisting of H, C1-6alkyl and N(R32a)-C1-6alkyl; R32a represents C1-6alkyl; m is 0, 1 or 2; n is 2; X1 is independently selected from group consisting of covalent bond, -C1-6alkyl and -C1-6alkyl-N(R33)-; X2 represents -N(R35)-; X3 represents -C(O)-; R33 represents C1-6alkyl; R35 represents H; Z1, Z2 are independently selected from group consisting of Z3 and -C(R37a)Z3aZ3b; R37a represents H; Z3, Z3a, Z3b are independently selected from group consisting of T1, T2, C1-6alkyl, C1-6alkyl-T1 and C1-6alkyl-T2; T1 represents phenyl; where T1 is optionally substituted with one or more R38; R38 being independently selected from group consisting of halogen, CN, R39, C(O)NH2, S(O)2NH2, OT3, C(O)N(R40)T3 and T3, T2 is selected from group consisting of C3-7cycloalkyl, indanyl, tetralinyl, heterocycle and heterobicycle, T2 optionally carries substitution with one or more R41, where R41 is independently selected from group consisting of halogen, R42, OH and T3; R39 is selected from group consisting of C1-6alkyl, O-C1-6alkyl, S-C1-6alkyl, C(O)N(R44)-C1-6alkyl, S(O)-C1-6alkyl and S(O)2-C1-6alkyl, where each C1-6alkyl optionally carries substitution with one or more R45, where R45 is independently selected from group consisting of F, N(R46R47) and T3; R42 represents C1-6alkyl, each C1-6alkyl optionally carries substitution with one or more R45, where R45 is independently selected from group consisting of F; R40, R46, R47 are independently selected from group consisting of H and C1-6alkyl; R44 represents H; T3 is selected from group consisting of T4 and T5; T4 represents phenyl, where T4 optionally carries substitution with one or more R51, where R51 is independently selected from group consisting of halogen, OR52, S(O)2N(R52R53), C1-6alkyl; R52, R53 are independently selected from group consisting of H and C1-6alkyl; T5 is selected from group consisting of heretocycle C3-7cycloalkyl, where T5 optionally carries substitution with one or more R54, where R54 represents C1-6alkyl; where heterocycle represents ring of cyclobutane, cyclopentane, cyclohexane, which can contain double bonds in number up to maximal, or aromatic or non-aromatic ring which is fully or partially saturated or unsaturated, and in which at least one carbon atom, maximally up to four carbon atoms, are substituted with heteroatom, selected from group including oxygen and nitrogen, and where ring is bound with remaining part of molecule through carbon or nitrogen atom; where heterobicycle represents heterocycle as stated above, which is condensed with phenyl or other heterocycle with formation of bicyclic ring system, on condition that the following compound is excluded from claim:3-amino-N-cyclohexyl-4-phenylbutyramide. Invention also relates to pharmaceutical composition based on compound of general formula (I) and to their application for manufacturing medication for treatment and/or prevention of conditions during which it is desirable to inhibit DPP-IV.

EFFECT: obtaining novel group of compounds possessing useful biological properties.

26 cl, 8 tbl, 193 ex

FIELD: chemistry.

SUBSTANCE: in arylpiperazinyl compounds of general formula , where R1 is unsubstituted alkyl or cycloalkyl; R2 and R3 independently hydrogen; lower alkyl; cycloalkyl; or -NR4R5, where R4 and R5 independently represent H, O, R6 or COR6, where R6 can represent lower alkyl or sulfonamidoalkyl; on condition that R2 and R3 both are not hydrogen; -atoms designated as bound with dotted line, taken together with atoms, to which they are joined, can form six-member ring; - Z represents N or C; - m equals 0, 1 or 2; - n equals 1, 2, 3, 4, 5 or 6; - p equals 0, 1, 2, 3 or 4. Compounds can be used for treatment of diseases, mediated directly or indirectly by 5-HT receptors. Such diseases are disorders of central nervous system.

EFFECT: increase of composition and method of treatment efficiency.

50 cl, 12 dwg, 2 tbl, 41 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

.FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their physiologically acceptable salts also possessing properties for decrease the blood sugar content. In compound of the formula (I) A means phenyl wherein phenyl residue can be substituted up to three times with fluorine (F), chlorine (Cl) and bromine (Br) atoms; R1 and R2 mean hydrogen atom (H); R3, R4, R5 and R6 mean independently of one another H, F, Cl, Br, -NO2, -O-(C1-C6)-alkyl, (C1-C6)-alkyl, -COOH; R7 means H, (C1-C6)-alkyl wherein alkyl can be substituted up to three times with -OH, -CF3, -CN, COOH, -COO-(C1-C6)-alkyl, -CO-NH2, -NH2, -NH-(C1-C6)-alkyl, -N-[(C1-C6)-alkyl]2, -NHCO-(C1-C6)-alkyl, -NHCOO-(C1-C6)-alkyl or -NHCOO-(C1-C4)-alkylenephenyl; in (CH2)m m can mean 0-6 and aryl means phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, pyridyl, indolyl, piperidinyl, tetrahydronapthyl, 2,3-dihydrobenzo[1,4]dioxynyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl wherein aryl residue can be substituted mono- or multiple with R9 wherein R9 means F, Cl, Br, -OH, -NO2, -CF3, -OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, -O-(C1-C6)-alkyl, -COOH, -COO-(C1-C6)-alkyl. Also, invention relates to a pharmaceutical composition and a method for preparing a medicinal agent.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

7 cl, 2 sch, 1 tbl, 293 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I) as separate stereoisomers and their mixtures, or their physiologically acceptable salts possessing with inhibitory effect on VIIa factor. In the general formula of compounds of the formula (I) m = 0, 1, 2, 3 or 4; n = 0, 1, 2 or 3; A represents halogen atom; X represents oxygen atom; R1 is chosen from hydrogen atom, (C1-C6)-alkoxycarbonyl and (C6-C14)-aryloxycarbonyl wherein all aryl groups are free or substituted with (C1-C6)-alkoxy-group; R2is chosen from hydrogen atom, (C1-C6)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl, R20 -(C1-C6)-alkyl, R20-(C6-C14)-aryl and R20-(C6-C14)-(C1-C4)-alkyl wherein R20 is chosen from hydroxycarbonyl, aminocarbonyl; R3 is chosen from hydrogen atom, cyano-, hydroxy-group and (C1-C6)-alkyl; R4 is chosen from (C1-C6)-alkyl, (C-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl, Het and Het-(C1-C4)-alkyl wherin alkyl, atryl and Het groups are free or substituted with one or some similar or different substitutes R10; R5 is chosen from hydrogen atom, (C1-C6)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl wherein alkyl and aryl groups are free or substituted with one or some similar or different substituted R10; or R4 and R5 in common with carbon atom with that they are bound form saturated or unsaturated 5-6-membered ring that represents carbocyclic ring or heterocyclic ring comprising 1 or 2 similar ring heteroatoms chosen from nitrogen and oxygen atoms and possibly condensed with one or two saturated or unsaturated carbocyclic ring system comprising from 5 to 10 ring atoms wherein the final R4(R5)C-group is free or substituted with one or some similar or different substitutes R10; R6 is chosen from hydrogen atom and hydroxy-group. Also, invention relates to a method for synthesis of compound of the formula (I) and pharmaceutical composition based on thereof. Compounds of the formula (I) can be used in preparing medicinal agents useful for inhibition or decreasing blood coagulation or inflammatory response or for using in treatment of cardiovascular disorders, thrombo-embolic diseases or restenosis.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

14 cl, 1 sch, 71 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein Ar represents phenyl substituted with a group taken among isobutyl, benzoyl, isopropyl, styryl, pentyl, (2,6-dichlorophenyl)-amino-group, α-hydroxyethyl, α-hydroxybenzyl, α-methylbenzyl and α-hydroxy-α-methylbenzyl; R represents hydrogen atom; X means linear (C1-C6)-alkylene, (C4-C6)-alkenylene, (C4-C6)-alkynylene optionally substituted with group -CO2R3 wherein R3 means hydrogen atom, group (CH2)m-B-(CH2)n wherein B means oxygen atom; m = 0; n means a whole number 2; or B means group -CONH; m means a whole number 1; n means a whole number 2 and so on; R1 and R2 are taken independently among group comprising hydrogen atom, linear (C1-C4)-alkyl, hydroxy-(C2-C3)-alkyl and so on. Invention proposes a method for preparing compounds of the formula (I). Invention proposes inhibitors of C5-induced hemotaxis of polymorphonuclear leukocytes and monocytes representing (R)-2-arylpropionic acid omega-aminoalkylamides of the formula (I). Also, invention relates to a pharmaceutical composition possessing inhibitory activity with respect to hemotaxis of polymorphonuclear leukocytes and monocytes and comprising compounds of the formula (I) in mixture with suitable carrier. Proposes (R)-2-arylpropionic acid omega-alkylamides are useful for inhibition of hemotaxic activation induced C5a and other hemotaxic proteins.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

18 cl, 3 tbl, 23 ex

The invention relates to pharmaceutically acceptable salts of the compounds of formula (I) or solvate specified salts in which the compound of formula (I) is in the form of (R)-enantiomer, (S)-enantiomer or the racemate

The invention relates to new derivatives of 1,2,3,4-tetrahydronaphthalene formula (I) as (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or solvate, where X is N or CH; Y is NR2-CH2, NR2-CO or CO-NR2; R2represents N or C1-C6-alkyl; R1represents N or C1-C6-alkyl; R3represents phenyl which may be mono - or Disaese4; R4represents H, halogen, CN, CF3WITH1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, or COR8; R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O; R9is1-C6-alkyl, ОСНF2HE, halogen, C1-C6-alkoxy, C1-C6-alkoxy - C1-C6-alkyl

The invention relates to a method of production of new chemical compounds, diamine consisting of aromatic and cycloaliphatic fragments, specifically disodium salt of N,N-bis-(4-amino-2-sulfophenyl)piperazine, which can be used as a monomer in producing high-strength heat-resistant cation-exchange materials

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with general formula (I), in which X1 is phenyl, 9-member bicyclic heteroaryl, containing S or O as heteroatoms, or 5-member heteroaryl, containing S or O as heteroatoms, each of which is optionally substituted with one or more substitutes, chosen from halogen or C1-6alkyl, which is optionally substituted with one or more halogens. X2 is phenyl, which is optionally substituted with one or more substitutes, chosen from halogen, or 5-member heteroaryl, containing S or O as heteroatoms. Ar is phenylene, which is optionally substituted with one or more substitutes, chosen from halogen, or C1-6alkyl, phenyl, C1-6alkoxy, each of which is optionally substituted with one or more halogens. Y1 is O or S, and Y2 represents O, Z represents -(CH2)n-, where n equals 1, 2 or 3. R1 is hydrogen or C1-6alkoxy and R2 is hydrogen, C1-6alkyl. The invention also relates to pharmaceutical salts of these compounds or any of their tautomeric forms, stereoisomers, stereoisomer mixtures, including racemic mixtures.

EFFECT: invention also pertains to use of these compounds as pharmaceutical compositions, with effect on receptors, activated by the peroxisome proliferator PPARδ subtype, and to pharmaceutical compositions, containing these compounds (I).

36 cl, 41 ex

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