Vinylogous acid derivatives as chymase inhibitors

FIELD: chemistry.

SUBSTANCE: claim describes novel vinylogous acid derivatives of formula , in which ring A is as defined in claim 1, R1 denotes hydrogen, C1-C6-alkyl or -NR'R", -( C0-C6-alkylene)-NR'R'', where R' and R" are independently selected from a group comprising hydrogen, C1-C6-alkyl, formyl, C1-C6-alkylcarbonyl; R2, R2' and R2" independently denote hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy group; R3 denotes phenyl; R4 denotes hydrogen, C1-C6-alkyl, optionally substituted phenyl or phenyl- C1-C6-alkyl, R5 denotes hydrogen or C1-C6-alkyl; as well as physiologically acceptable salts thereof.

EFFECT: compounds inhibit chymase and can be used as medicinal agents.

15 cl, 27 ex

 

The present invention relates to new minilogues derivatives of acids of formula (I),

in which

And denotes a phenyl ring, or

heteroaryl ring, which is a monocyclic aromatic ring containing 5 or 6 ring atoms containing 1 or

2 ring heteroatoms selected from the group comprising N, O and S, the rest are atoms, or

heterocyclyl ring, which is a non-aromatic monocyclic ring containing 5 or 6 ring atoms containing 1 or 2 ring heteroatoms selected from the group comprising N and S(O)n(where n is a whole number equal to from 0 to 2), the rest are atoms With one of the ring carbon atoms heterocyclyl ring optionally replaced by a carbonyl group;

R1denotes hydrogen, halogen, a nitro-group, a cyano, an amino group, a C1-C6-alkyl, heteroalkyl,3-C7-cycloalkyl,2-C6alkenyl,2-C6-quinil, the hydroxy-group, C1-C6-alkoxygroup,

-R NR'r", -(C0-C6-alkylen)-R NR'r”where R' and R" are independently selected from the group comprising hydrogen, C1-C6-alkyl, heteroalkyl, formyl, C1-C6-alkylsulphonyl, optionally substituted C3-C7-recloak carbonyl, optionally substituted arylcarbamoyl, optionally substituted heteroarylboronic, optionally substituted heterocalixarenes, C1-C6-alkylsulfonyl, optionally substituted C3-C7-cycloalkylcarbonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylboronic and optionally substituted heterocyclisation, or

-(C0-C6-alkylene)-or SIG', where R' denotes hydrogen, C1-C6-alkyl, heteroalkyl, formyl or C1-C6-alkylsulphonyl;

R2, R2'and R2"independently represent hydrogen, halogen, a cyano, a nitro-group, amino group, mono - or di-C1-C6-the alkyl substituted amino group, a C1-C6-alkyl, C2-C6alkenyl, C2-C6-quinil, heteroalkyl, the hydroxy-group or C1-C6-alkoxygroup;

R3denotes hydrogen, halogen, a cyano, a nitro-group, amino group, mono - or di - C1-C6-the alkyl substituted amino group, a C1-C6-alkyl, C2-C6alkenyl,2-C6-quinil, heteroalkyl, the hydroxy-group, C1-C6-alkoxygroup, optionally substituted C3-C7-cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optional C is displaced With 3-C7-cycloalkyl-C1-C6-alkyl, optionally substituted aryl-C1-C6-alkyl, optionally substituted heteroaryl-C1-C6is alkyl or optionally substituted heterocyclyl-C1-C6-alkyl;

R4denotes hydrogen, halogen, a cyano, a nitro-group, amino group, mono - or di - C1-C6-the alkyl substituted amino group, a C1-C6-alkyl, C2-C6alkenyl,2-C6-quinil, heteroalkyl, the hydroxy-group, C1-C6-alkoxygroup, optionally substituted C3-C7-cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C3-C7-cycloalkyl-C1-C6-alkyl, optionally substituted aryl-C1-C6-alkyl, optionally substituted heteroaryl-C1-C6is alkyl or optionally substituted heterocyclyl-C1-C6-alkyl;

R5denotes hydrogen, halogen or C1-C6-alkyl; or R4and R5together with the carbon atom to which they are attached, form an optionally substituted C3-C7-cycloalkyl ring or optionally substituted heterocycles ring;

and their prodrugs and pharmaceutically acceptable salts.

In addition, the present invention relates to a method and intermediate product to obtain the above compounds, to pharmaceutical preparations which contain such compounds, to the use of these compounds for the preparation of pharmaceutical preparations, and also to a method for producing an intermediate product.

The compounds of formula (I) inhibit himizu. Chymase is semipretioase, the provision of which is limited only by the subgroup of mastocytes (Marticle- mastocyte). Chymase is only activated by the activation and degranulation of mastocyte that limits the activity of the enzyme fabrics, containing Marticle. Chymase specifically cleaves a number of related pathologies substrates (Raymond, W.W., S.W.Ruggles, et al.; JBC 2003 278(36):34517-34524) and it can activate angiotensin II, endothelin, TGFb, I11, SCF, collagenase and destroy proteins, such as thrombin, FN, APO A1,2. These characteristics make himizu attractive target in the case of allergic, inflammatory and fibrotic diseases. In fact, a number of successful animal studies using chymase inhibitors have demonstrated efficacy in the case of allergic manifestations in animals, lesions, blood vessels and atherosclerosis (Doggrell SA, Wanstall JC Can J Physiol Pharmacol. 2005 Feb; 83(2):123-30; Lindstedt KA, Kovanen PT. Curr Opin Lipidol. 2004 Oct; 15(5):567-73; Reed CE, Kita H.J Allergy dm Immunol. 2004 Nov; 114(5):997-1008; Takai S, et al. Eur J Pharmacol. 2004 Oct 6;501(1-3):1-8; Takai S, et al, Trends Pharmacol Sci. 2004 Oct; 25(10):518-22; Takai S, Miyazaki M. Curr Vase Parmacol. 2003 Jun; 1(2):217-24).

Thus, inhibition of chymase seems to be a useful technique impact in Allergy, asthma, obstructive lesions of peripheral artery disease, critical limb ischemia, patients with unstable atherosclerotic plaques, unstable angina, congestive heart failure, the left ventricle hypertrophy, ischemic reperfusion lesions, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable bowel syndrome, Crohn's disease, wound healing (burns/ulcers in diabetes/KICK (critical limb ischemia).

The present invention relates to new compounds of the formula (I)which are inhibitors of chymase.

Unless otherwise stated, the definitions below are intended to illustrate and define the values and scope of the various terms used in the description of the present invention.

The term "halogen" means fluorine, chlorine, bromine or iodine, with chlorine and fluorine are preferred.

The term "C1-C6alkyl", alone or in combination with other groups, means having a branched or linear chain monovalent alkyl radical containing from 1 to 6 carbon atoms. Examples of values for this term are such radicals as methyl, who Tyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl. C1-C4Alkyl is more preferable.

The term "heteroalkyl" means C1-C6is alkyl containing one or more substituents independently selected from the group comprising nitro-group, a hydroxy-group, halogen, cyano, C1-C6-alkoxygroup, formyl, C1-C6-alkylsulphonyl, carboxypropyl, C1-C6-alkylthio, C1-C6-alkylsulfonyl, C1-C6-alkylsulfonyl, amino, and mono - or di - C1-C6-the alkyl substituted amino group. Examples of values for this term are such radicals, such as 2-hydroxyethyl, performer. C1-C6-Alkyl substituted by one hydroxy-group or one to three same or different halogen atoms, is preferred.

The term "C3-C7-cycloalkyl", alone or in combination with other groups, means saturated monovalent cyclic hydrocarbon radical containing from 1 to 7 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclohexyl.

The term "C1-C6-alkoxygroup", alone or in combination with other groups, means a group R'-O-in which R' represents C1-C6-alkyl.

The term "C2-C6alkenyl", alone or in comb the nation with other groups, means having a branched or linear chain hydrocarbon residue containing a double bond containing from 2 to 6 carbon atoms, such as, for example, ethinyl, 2-propinyl.

The term "C2-C6-quinil", alone or in combination with other groups, means having a branched or linear chain hydrocarbon residue containing a triple bond containing from 2 to 6 carbon atoms, such as, for example, ethinyl, 2-PROPYNYL.

The term "C0-C6-alkylene" means communication or with a branched or linear chain divalent saturated aliphatic hydrocarbon group containing from 1 to 6 carbon atoms. With0-Alkylen means the connection.

The term "aryl", alone or in combination with other groups, means a phenyl or naftalina group, preferably phenyl group.

The term "heterocyclyl", alone or in combination with other groups, means a non-aromatic mono - or bicyclic radicals containing from 3 to 8 ring atoms in which 1 or 2 ring atoms are heteroatoms selected from the group comprising N, O and S(O)n(where n is a whole number equal to from 0 to 2), the rest are atoms C.

The term "heteroaryl" means a monocyclic or bicikliski radical containing from 5 to 12 ring atoms, sod is Rashi at least one aromatic ring, containing 1, 2 or 3 ring heteroatoms selected from the group comprising N, O and S, the remaining atoms are C. Preferably, if the position of the joining heteroaryl radical is an aromatic ring.

The term "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted heterocyclyl" and "optionally substituted C3-C7-cycloalkyl" means, respectively, aryl, heteroaryl, heterocyclyl and C3-C7-cycloalkyl, optionally containing one or more substituents independently selected from the group comprising halogen, a nitro-group, a cyano, an amino group, a C1-C6-alkyl, C2-C6alkenyl, C2-C6-quinil, the hydroxy-group, C1-C6-alkoxygroup, mono - or di-C1-C6-the alkyl substituted amino group and heteroalkyl.

Preferred radicals for chemical groups, the definition of which is given above are those that are specifically mentioned in the examples as examples.

The compounds of formula (I) can form pharmaceutically acceptable salts joining with acids. Examples of such pharmaceutically acceptable salts are salts of compounds of formula (I) with physiologically compatible inorganic acids such as hydrochloric acid, sulfuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulfonate acid, n-toluensulfonate acid, acetic acid, lactic acid, triperoxonane acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The term "pharmaceutically acceptable salt" means those salts. The compounds of formula (I)which contain a COOH group, may also form salts with bases. Examples of such salts are salts of alkali and alkaline earth metals and ammonium, such as, for example, salts of Na, K, CA and trimethylammonium. The term "pharmaceutically acceptable salt" means and such salts. Salt accession with acids described above are preferred.

"Optional" or "optional" means that the subsequent described event or circumstance may but should not be, and that the description includes instances where the event or circumstance is and when it is not carried out. For example, "aryl group optionally substituted alkyl group"means that the alkyl group may, but need not be contained, and the description includes instances when the aryl group is substituted by an alkyl group, and cases where the aryl group is not substituted by an alkyl group.

"The pharmacist is Cesky acceptable excipient" means an excipient, which is suitable for the preparation of pharmaceutical compositions, generally safe, non-toxic and biologically and in other respects not junk, and includes inert fillers that are acceptable for veterinary use and for use in pharmaceuticals intended for people. "Pharmaceutically acceptable excipient" as used in the present invention includes one or more than one such excipient.

Compounds that have identical molecular formulas but differ in the nature and sequence of the binding of atoms or the arrangement of atoms in space are referred to as "isomers". Isomers that differ in the arrangement of atoms in space are called stereoisomers". Stereoisomers that are not mirror images of each other, are called "diastereoisomers" and those mirroring which is not subject to each other, are called "enantiomers". If the compound contains an asymmetric center, for example, if the carbon atom is linked to four different groups, the formation of a pair of enantiomers. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by rules of the sequence of R - and S-configurations Cana, And the gold and Prelog or by specifying as the molecule rotates the plane of polarized light, i.e. whether it is programada or levogyrate (i.e. are indicated (+) or (-)-isomers respectively). Chiral compound can exist as individual enantiomers or as mixtures thereof. A mixture containing equal amounts of the enantiomers is called a racemic mixture.

The compounds of formula (I) may contain one or more asymmetric centers. If not stated otherwise, the description or the name of a particular compound in the specification and the claims includes the individual enantiomers and mixtures thereof, and racemic and others, as well as individual epimere and their mixture. Methodologies for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see discussion in the main 4 publication "Advanced Organic Chemistry", 4th edition, J. March, John Wiley and Sons, New York, 1992).

Although the above describes the most extensive variant of the present invention, the compounds of formula (I)containing some radicals, are preferred.

In the compounds of formula (I),

more preferably (a), (d), (e) or (f), more preferably (a), (e) or (f), and particularly preferred is (a).

In the compounds of formula (I), R3preferably represents C1With 6-alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C1-C6is alkyl or optionally substituted heteroaryl-C1-C6-alkyl, more preferably, when R3represents C1-C6-alkyl, phenyl, optionally substituted by 1-3 fluorine atoms, heteroaryl, optionally substituted by 1-3 fluorine atoms, where heteroaryl is a monocyclic aromatic radical containing 5 or 6 ring atoms containing 1 or 2 ring nitrogen atom, or phenyl-C1-C6-alkyl, and R3preferably denotes phenyl.

In the compounds of formula (I) R1preferably represents hydrogen, C1-C6-alkyl, C1-C6-alkoxygroup, -(C0-C6-alkylen)-R NR'r"where R' and R" are independently selected from the group comprising hydrogen, formyl, C1-C6-alkylsulphonyl, optionally substituted arylcarbamoyl, optionally substituted heteroarylboronic, optionally substituted arylsulfonyl and optionally substituted heteroarylboronic or -(C0-C6-alkylene)-or SIG', where R' denotes hydrogen or C1-C6-alkylsulphonyl. More preferably, if R1represents C1-C6-alkyl, -(C2-C6-alkylen)-R NR'r"where R' and R" are independently selected from the group comprising water the rod, formyl, acetyl, arylcarbamoyl, where aryl optionally substituted with one or two performanceline groups, and arylsulfonyl or -(C2-C6-alkylene)-or SIG', where R' denotes hydrogen or acetyl. Even more preferably, if R1refers to 2-amino-ethyl, 2-acetylaminophenol, 2-(N-formyl-N-methylamino)ethyl, 2-acetylamino-2,2-dimethylethyl, methyl, isopropyl or 2-hydroxyethyl. Preferably, if R1denotes methyl, 2-acetylaminophenol, 2-acetylamino-2,2-dimethylethyl or 2-(N-formyl-N-methylamino)ethyl.

In the compounds of formula (1), R2, R2'and R2"preferably independently represent hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxygroup. More preferably, if two of R2, R2'and R2"denote hydrogen and the third one denotes hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxygroup. Even more preferably, if two of R2, R2'and R2"denote hydrogen and the third one denotes hydrogen, chlorine, fluorine, methyl, ethyl or methoxy group. Preferably, if two of R2, R2'and R2"denote hydrogen and the third one denotes hydrogen, fluorine or methyl.

In the compounds of formula (1), R4preferably represents hydrogen, C1-C6-alkyl, optionally substituted C3-C7-cycloalkyl, neobyazatelnostyu aryl, optionally substituted C3-C7-cycloalkyl-C1-C6is alkyl or optionally substituted aryl-C1-C6-alkyl; or R4and R5together with the carbon atom to which they are attached, form an optionally substituted C3-C7-cycloalkyl ring. More preferably, if R4stands With1-C6-alkyl, optionally substituted aryl or optionally substituted aryl-C1-C6-alkyl, and R5denotes halogen or C1-C6-alkyl. Preferably, if R4denotes phenyl or 4-were, and R5denotes methyl.

The preferred connection is proposed in the present invention, is a compound of formula (I), which is a

N-(2-{2-[(2-Hydroxy-3-methyl-4-oxo-3-phenylcinnamic-1-enyl)-phenylmethyl]-6-methyl-1H-indol-3-yl}-1,1-dimethylethyl)-ndimethylacetamide,

3-Hydroxy-4-methyl-2-[(3-methyl-1H-indol-2-yl)-phenylmethyl]-4-phenylcinnamic-2-Aenon

2-[(3,5-Dimethyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-phenylcinnamic-2-Aenon

2-[(3,6-Dimethyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-phenylcinnamic-2-Aenon

2-[(5-fluoro-3-methyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-phenylcinnamic-2-Aenon

N-{2-[(2-Hydroxy-3-methyl-4-oxo-3-phenylcinnamic-1-enyl)-phenylmethyl]-6-methyl-1H-indol-3-ylmethyl}-acetamide", she

3-Hydroxy-4-methyl-2-[(3-m is Teal-1H-indol-2-yl)-phenylmethyl]-4-p - taillecavat-2-Aenon

2-[(3,5-Dimethyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-p-taillecavat-2-Aenon

2-[(3,6-Dimethyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-p-taillecavat-2-Aenon

2-[(5-fluoro-3-methyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-p-taillecavat-2-Aenon

N-{2-[(2-Hydroxy-3-methyl-4-oxo-3-p-taillecavat-1-enyl)-phenylmethyl]-6-methyl-1H-indol-3-ylmethyl}-acetamid or

N-{2-[(2-Hydroxy-3-methyl-4-oxo-3-p-taillecavat-1-enyl)-phenylmethyl]-6-methyl-1H-indol-3-ylmethyl}-N-methylformamide.

Connections proposed in the present invention, can be obtained, for example, according to the General methods of synthesis described below.

General procedure for the synthesis of

I) the compounds of formula (I), in which

means

(where R1, R2, R2'and R2”are as defined above) can be obtained in accordance with the following scheme 1:

R3, R4and R5are as defined above. AG stands

and Ah' means

,

where R1, R2, R2', R2”are as defined above.

The combination of diketone II (exists as an equilibrium mixture of keto - and enol forms), aldehyde III and aromatic compounds IV with the formation of vinyl is logical acid 1 can be held in the solvent, such as CH3JV, or in acid, such as carboxylic acid, for example formic acid, or preferably acetic acid, at a temperature in the range 22-100°C, preferably at 22°C for 1-20 hours

II) Compounds of the formula (I),

in which

means

or

(where R1, R2, R2'and R2"are as defined above), can be obtained in accordance with the following scheme 2:

R3, R4and R5are as defined above. AG stands

or

and Ar' denotes

or

(where R1, R2, R2'and R2"are as defined above).

Aromatic compound AG IV, such as 2-halogen-substituted derivatives of naphthalene or derivatives benzothiophene, you can lichirovarc in position 2 alkyllithium reagent, such as n-utility, in a solvent such as, for example, ethyl ether, or preferably tetrahydrofuran at a temperature from -100 to 60°C., preferably at -80°C. the Obtained litigiously intermediate product, you can enter into reaction with the aldehyde II at a temperature of from -80 to 22°C and to obtain alcohol V.

Alcohol V you can enter into reaction with the diketone II in the presence of carboxylic acids, for example acetic acid, or, preferably, triperoxonane acid in a solvent such as a simple ether or, preferably, dichloromethane at a temperature in the range 22-50°C., preferably at 22°C for 1-20 hours, and get vinylogous acid I.

III) the parent substance of the formula II can be obtained in accordance with the following scheme 3:

R4and R5are as defined above.

Acid VI can be converted into the acid chloride acid by standard methods using oxalicacid or, preferably, thionyl chloride to obtain the acid chloride of the acid VII. The acid chloride of the acid can be introduced into the reaction ethoxyacetylene in the presence of a base, such as alkylamine, preferably triethylamine, in a solvent such as a simple ether, preferably diethyl ether, at a temperature of 0-40°C., preferably at 40°C, and to obtain ethyl ester VIII. The hydrolysis of the ethyl ester VIII can be carried out with the help of a strong inorganic acid, preferably hydrochloric acid in a solvent such as a simple ether, preferably tetrahydrofuran at a temperature of 0-60°C., preferably at 22°C and get diketone II.

The original substance of the formula I can be obtained in accordance with the following literature:

1) Brand, Stephen et al., Organic Letters (2003), 5(13), 2343-2346.

IV) the parent substance of the formula III are commercially available.

V) most of the aromatic compounds of the formula IV are commercially available or specialist in the art and may be obtained on the basis of their training. The compounds of formula IV can also be obtained in accordance with the following literature:

2) Kreighbaum, William E. et al., J. Med. Chem. (1980), 23(3), 285-9.

3) Yang, Shyh-Chyun et al., Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (1999), 38B(8), 897-904.

4) Tsuchiya, Michihiro et al., international patent application, WO8200032 (1982).

5) Hengartner, Urs et al., Journal of Organic Chemistry (1979), 44(22), 3741-7.

6) Somei, Masanori et al., Heterocycles (1992), 33(1), 77-80.

VI) All of the source materials of formula VI are commercially available.

As indicated above, the compounds of formula (I) are active compounds and inhibit himizu. Therefore, these compounds prevent the activation of angiotensin II, endothelin, TGFb, I11, SCF, collagenase and destruction of proteins, such as thrombin, FN, APO A1,2. Therefore they can be used for the prevention and/or treatment of allergic, inflammatory and/or fibrotic diseases, such as allergies, asthma, occlusive peripheral artery disease, critical limb ischemia, patients with unstable atherosclerotic plaques, unstable angina, congestive heart failure, left ventricular hypertrophy, ischemic who reperfusion lesion, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable bowel syndrome, Crohn's disease, atherothrombosis and/or burns/ulcers in diabetes/KICK.

Prevention and/or treatment of allergic, inflammatory or fibrotic diseases, preferably of atherothrombosis or asthma, is the preferred reading.

Therefore, the present invention also relates to pharmaceutical compositions comprising a compound as defined above, and pharmaceutically acceptable excipient.

The present invention also relates to the compounds described above, intended for use as therapeutically active substances, preferably as therapeutically active substances for the treatment and/or prevention of allergic, inflammatory and/or fibrotic diseases, more preferably as therapeutically active substances for the treatment and/or prevention of Allergy, asthma, occlusive peripheral artery disease, critical limb ischemia, patients with unstable atherosclerotic plaques, unstable angina, congestive heart failure, the left ventricle hypertrophy, ischemic reperfusion lesions, stroke, cardiomyopathy, restenosis, rheumatoid the wow arthritis, diabetic nephropathy, irritable bowel syndrome, Crohn's disease, atherothrombosis and/or burns/ulcers in diabetes/KICK.

The present invention also relates to the use of compounds described above, for preparing medicinal products intended for therapeutic and/or prophylactic treatment of allergic, inflammatory and/or fibrotic diseases, preferably a therapeutic and/or prophylactic treatment of allergies, asthma, occlusive peripheral artery disease, critical limb ischemia, patients with unstable atherosclerotic plaques, unstable angina, congestive heart failure, the left ventricle hypertrophy, ischemic reperfusion lesions, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable bowel syndrome, Crohn's disease, atherothrombosis and/or burns/ulcers in diabetes/KICK. These drugs contain the connection described above.

The present invention also relates to a method and intermediate products for producing compounds of formula (I), as well as to a method for producing intermediate products.

Inhibition of chymase compounds proposed in the present invention, it is possible to demonstrate through research peptide the second substrate, described below in the present invention.

For chymase selected substrate constituting containing 4 amino acid peptide AAPF, a standard substrate for connection type chymotrypsin (succinyl-l-l-Pro-Phe-[7-amino-4-methylcoumarin];Lockhart BE, et al., "Recombinant human mast-cell chymase: an improved procedure for expression in Pichia pastoris and purification of the highly active enzyme." iotechnol Appl Biochem, published as immediate publication 26 May 2004 as manuscript BA20040074). Peptide purity 95% synthesized firm Bachem, Bubendorf, Switzerland)). Himizu isolated from mastocytes human skin, obtained from the company Calbiochem (Merck Biosciences, San Diego, California, USA). Used buffer for analysis, containing 0.15 M NaCl, 0,05 m, Tris-HCl [Tris - Tris(hydroxyethylaminomethyl)], of 0.05% CHAPS (3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate), 0.1 mg/ml heparin (sodium salt of heparin, Sigma, of the mucous membrane of the intestine of the pig), 0.02 mm substrate AAPF, 1 nm chymase at pH 7.4. The study was performed in 96-well plates (Packard Optiplate) in the amount equal to 0.05 ml, at room temperature. Chymase was assessed by the initial velocity amplification fluorescence in 340/440 nm (excitation/emission) of free 7-amino-4-methylcoumarin released from the substrate. The inhibition activity of any abscopal compounds was determined after held within 30 min pre-incubation with hemati at room temperature in buffer for analysis, to which neprobovali substrate AAPF. Then was added the substrate AAPF at the specified concentration and started investigation.

The values of the IC50for active compounds proposed in the present invention preferably comprise from about 1000 to 1 nm, preferably from about 50 to 1 nm.

ExampleIC50(nm)
Example 327
Example 634
Example 1025
Example 138

The compounds of formula (I) and/or their pharmaceutically acceptable salts can be used as medicines, for example, in the form of pharmaceutical preparations for enteral, parenteral or local administration. They can be administered, e.g. orally, for example in the form of tablets, coated tablets, pills, capsules made of hard or soft gelatin, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in form of injectable solutions or solutions for injection, or topically, for example in the form of ointments, creams or oils. Oral administration is preferred.

The preparation of the pharmaceutical is a mini-preparations can be made by way which famous person skilled in the art, by making the above compounds of formula 1 and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, Galanova dosage form together with suitable non-toxic, inert, therapeutically compatible solid or liquid carriers and, if necessary, with conventional pharmaceutical auxiliary substances.

Suitable carriers are not only inorganic carriers and organic carriers. So, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts etc can be used as carriers for tablets, coated tablets, pills and capsules of hard gelatin. For soft gelatin capsules of suitable carriers are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (however, depending on the nature of the active substance in the case of soft gelatin capsules from the media usually not needed). Carriers suitable for the preparation of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and other Media suitable for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils. Carriers suitable for when positories, are, for example, natural or hardened oils, waxes, fats and semi-solid and liquid polyols. Carriers suitable for drugs local actions are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, glycols and derivatives of cellulose.

As pharmaceutical excipients are included in the review of conventional stabilizers, preservatives, wetting and emulsifying agents, which improves the consistency of the agents for improving taste agents, salts for regulating the osmotic pressure, buffer substances, soljubilizatory, dyes and masking agents and antioxidants.

The dosage of the compounds of formula (I) can vary within wide limits depending on the treated disease, age and individual condition of the patient and route of administration and, of course, in each specific case will vary according to individual needs. For adult patients in the review included daily dose, approximately 1 to 1000 mg, preferably from about 1 to 300 mg, depending on the severity of the disease and the precise pharmacokinetic profile of the compound can be introduced in the form of one or more doses per day, for example in the form of 1-3 single the lake.

The pharmaceutical preparations normally contain about 1-500 mg, preferably 1-100 mg of the compounds of formula (I).

Examples

The following examples are intended to further illustrate the present invention. However, they are not intended for any limitation of the scope of the present invention.

General procedure a: Getting diketone II

A1. The mixture of acid VI (30 mmol) in toluene (10 ml) was treated with thionyl chloride (90 mmol) and boiled under reflux for about 1 h until gas evolution stops. The mixture is evaporated to dryness and the obtained acid chloride of the acid VII which was used without further purification.

A2. To a solution of the carboxylic acid VII (30 mmol) and ethoxyacetylene (40% in hexane, 60 mmol) in diethyl ether (70 ml) at 22°C under stirring were added triethylamine (50 mmol) and continued stirring while boiling under reflux for 20 hours, the Suspension was filtered, the filtrate evaporated and the residue was chromatographically on the silicon dioxide and received complex ethyl ester VIII.

A3. The complex mixture of ethyl ester VIII (2 mmole) and aqueous hydrochloric acid (25%, 1.5 ml) in tetrahydrofuran (2 ml) was stirred at 22°C for 16 hours the Mixture was evaporated and the residue was subjected to distribution between aqueous hydrochloric acid (1 ad) and e is racedata. The organic layer is evaporated to dryness and chromatographically on the silicon dioxide and received diketone II.

General procedure b: Getting alcohols V

To a solution of substituted 2-bromonaphthalene (10 mmol) or substituted benzothiophene (10 mmol) in tetrahydrofuran (150 ml) at -78°C was added n-utility (1.6 M in n-hexane, 11 mmol) and stirring continued at -78°C for 1 h (in the case of substituted benzothiophenes stirring was continued at 22°C., then was cooled to -78°C). The mixture was treated with a solution of aldehyde III (10 mmol) in tetrahydrofuran (20 ml) and stirring was continued for 30 minutes the Reaction was stopped with saturated solution of NH4Cl and the mixture was extracted with ethyl acetate. The organic layer is evaporated to dryness and the residue was chromatographically on the silicon dioxide and received alcohols V.

General procedure C: Reaction mix diketone II, aldehyde III and aromatic compounds, such as indole IV

A solution of diketone II (1 mmol), aldehyde III (1.3 mmole) and indole IV (1 mmol) in acetic acid (4 ml) was stirred at 22°C for 16 hours, the Suspension was filtered and the residue was washed with pentane. If you do not fell the precipitate, the solution was purified by using preparative VIEH (high performance liquid chromatography (RP-18, CH3CN/H2O, gradient mode) and got vinylogous acid I

General procedure D: Reaction with Etania diketone II and alcohol V

A solution of diketone II (0.2 mmole) and ethanol V (0.2 mmole) in dichloromethane (2 ml) was added to triperoxonane acid (0.4 mmole) and stirring was continued at 22°C for 6 hours, the Suspension is evaporated and the residue was washed with n-pentane. If you do not fell the precipitate, the solution was purified by using preparative VIEH (RP-18, CH3SP/N2Oh, gradient mode) and got vinylogous acid I.

Example 1

N-(2-{2-[(2-Hydroxy-3-isobutyl-3-methyl-4-oxacyclic-1-enyl)-phenylmethyl]-6-methyl-1H-indol-3-yl}-1,1-dimethylethyl)-ndimethylacetamide

1.1. Using a common methodology And 2,4-dimethylpentane acid was converted into 2-isobutyl-2-methylcyclobutane-1,3-dione, which was obtained as a brown oil. MS (mass spectrometry): 153,4 ([M-H]-).

1.2. A solution of 1,1-dimethyl-2-(6-methyl-1H-indol-3-yl)-ethylamine(2 mmole, obtained as described in publication 2) and acetic anhydride (2.2 mmole) in dichloromethane (3 ml) was treated with triethylamine (6 mmol) and the mixture was stirred at 22°C for 18 hours the Mixture was washed with an aqueous solution of hydrochloric acid (1 ad), the organic layer was dried and evaporated and obtained N-[1,1-dimethyl-2-(6-methyl-1H-indol-3-yl)-ethyl]-ndimethylacetamide in the form of a brown solid. MS: 243,2 ([M-H]-).

1.3. Using a common methodology With 2-isobutyl-2-methylcyclobutane-1,3-dione were introduced into a reaction with benzo is ledegem and N-[1,1-dimethyl-2-(6-methyl-1H-indol-3-yl)-ethyl]-ndimethylacetamide and received N-(2-{2-[(2-hydroxy-3-isobutyl-3-methyl-4-oxocyclopent-1-enyl)-phenylmethyl]-6-methyl-1H-indol-3-yl}-1,1-dimethylethyl)-ndimethylacetamide in the form of a pale brown solid substances. MS: 485,6 ([M-H]-).

Example 2

N-(2-{2-[(3-Benzyl-2-hydroxy-3-methyl-4-oxocyclopent-1-enyl)-phenylmethyl]-6-methyl-1H-indol-3-yl}-1,1-dimethylethyl)-ndimethylacetamide

Using a common methodology With 2-benzyl-2-methylcyclobutane-1,3-dione (publication 1) was introduced into the reaction with benzaldehyde and N-[1,1-dimethyl-2-(6-methyl-1H-indol-3-yl)-ethyl]-ndimethylacetamide (example 1.2) and obtained the desired compound as a red solid. MS: 519,5 ([M-H]-).

Example 3

N-(2-{2-[(2-Hydroqui-3-methyl-4-oxo-3-phenylcinnamic-1-enyl)-phenylmethyl]-6-methyl-1 H-indol-3-yl}-1,1-dimethylethyl)-ndimethylacetamide

Using a common methodology With 2-methyl-2-vinylcyclopentane-1,3-dione (publication 1) was introduced into the reaction with benzaldehyde and N-[1,1-dimethyl-2-(6-methyl-1H-indol-3-yl)-ethyl]-ndimethylacetamide (example 1.2) and obtained the desired compound in the form of a pale yellow solid. MS: 505,5 ([M-H]-).

Example 4

N-(2-{2-[(2-Hydroxy-3-methyl-4-oxo-3-p-taillecavat-1-enyl)-phenylmethyl]-6-methyl-1H-indol-3-yl}-1,1-dimethylethyl)-ndimethylacetamide

4.1. Using General procedure a 2-p-tolylpropan acid was converted into 2-methyl-2-p-taillecavat-1,3-dione, which was obtained as a brown oil. MS: 187,4 ([M-H]-).

4.2. Using a common methodology With 2-methyl-2-p-taillecavat-1,3-dinwoodie in the reaction with benzaldehyde and N-[1,1-dimethyl-2-(6-methyl-1H-indol-3-yl)-ethyl]-ndimethylacetamide (example 1.2) and obtained N-(2-{2-[(2-hydroxy-3-methyl-4-oxo-3-p-taillecavat-1-enyl)-phenylmethyl]-6-methyl-1H-indole-3-yl}-1,1-dimethylethyl)-ndimethylacetamide in the form of a pale yellow solid. MS: 519,5 ([M-H]-).

Example 5

N-[2-(2-{[3-(4-Chlorophenyl)-2-hydroxy-3-methyl-4-oxocyclopent-1-enyl]-phenylmethyl}-6-methyl-1H-indol-3-yl)-1,1-dimethylethyl]-ndimethylacetamide

5.1. Using General procedure a 2-(4-chlorophenyl)-propionic acid was converted into 2-(4-chlorophenyl)-2-methylcyclobutane-1,3-dione, which was obtained as a brown oil. MS: 206,9 ([M-H]-).

5.2. Using a common methodology With 2-(4-chlorophenyl)-2-methylcyclobutane-1,3-dione were introduced into the reaction with benzaldehyde and N-[1,1-dimethyl-2-(6-methyl-1H-indol-3-yl)-ethyl]-ndimethylacetamide (example 1.2) and obtained N-[2-(2-{[3-(4-chlorophenyl)-2-hydroxy-3-methyl-4-oxocyclopent-1-enyl]-phenylmethyl}-6-methyl-1H-indol-3-yl)-1,1-dimethylethyl]-ndimethylacetamide in the form of a pale yellow solid. MS: 539,5 ([M-H]-).

Example 6

3-Hydroxy-4-methyl-2-[(3-methyl-1H-indol-2-yl)-phenylmethyl]-4-phenylcinnamic-2-Aenon

Using a common methodology With 2-methyl-2-vinylcyclopentane-1,3-dione (publication 1) was introduced into the reaction with benzaldehyde and 3-methyl-1H-indole was obtained the desired compound as a colourless solid. MS: 392,3 ([M-H]-).

Example 7

2-[(3,5-Dimethyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-phenylcinnamic-2-Aenon

Using a common methodology With 2-methyl-2-paneltitle the utan-1,3-dione (publication 1) was introduced into the reaction with benzaldehyde and 3,5-dimethyl-1H-indole (publication 3) and obtained the desired compound as a colourless solid. MS: IS 406.5 ([M-H]-).

Example 8

2-[(3,6-Dimethyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-phenylcinnamic-2-Aenon

Using a common methodology With 2-methyl-2-vinylcyclopentane-1,3-dione (publication 1) was introduced into the reaction with benzaldehyde and 3,6-dimethyl-1H-indole (publication 4) and obtained the desired compound as a colourless solid. MS: TO 406.4 ([M-H]-).

Example 9

2-[(5-fluoro-3-methyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-phenylcinnamic-2-snon

Using a common methodology With 2-methyl-2-vinylcyclopentane-1,3-dione (publication 1) was introduced into the reaction with benzaldehyde and 5-fluoro-3-methyl-1H-indole was obtained the desired compound as a colourless solid. MS: 410,3 ([M-H]-).

Example 10

N-{2-[(2-Hydroxy-3-methyl-4-oxo-3-phenylcinnamic-1-enyl)-phenylmethyl]-6-methyl-1H-indol-3-ylmethyl}-ndimethylacetamide

10.1. To a solution of 6-methyl-1H-indole-3-carbaldehyde (0.96 g, publication 5) in ethanol (30 ml) at 22°C was added gidroxinimesoulid (0,46 g) and sodium acetate (0.54 g) and the mixture was stirred for 3 hours the Mixture is evaporated and the residue triturated with water and with a mixture of dichloromethane/n-heptane (1:1) and was dried and obtained 6-methyl-1H-indol-3-carbaldehyde (0.96 g) as a pink solid. MS: 175,3 ([M+H]+).

10.2. To a mixture of 6-methyl-1H-indol-3-CT is aldehydesin (0.66 g) and NiCl 2·6H2O (0.97 g) in methanol (60 ml) at 22°C. portions were added to borohydride sodium (totaling 3.04 g). The suspension was filtered and the filtrate evaporated. The residue was subjected to distribution between aqueous solutions of NH3(1%) and ethyl acetate, the organic layer was dried and evaporated and obtained the crude S-(6-methyl-1H-indol-3-yl)-methylamine as a yellow semi-solid substances (0.68 g).

10.3. To a solution of S-(6-methyl-1H-indol-3-yl)-methylamine (0.24 g) in dichloromethane (4 ml) was added acetic anhydride (0,14 ml) and pyridine (0,13 ml) and stirring was continued at 22°C for 20 minutes the Mixture was washed in an aqueous solution of Hcl (1 ad), the organic layer was dried and evaporated. The residue was chromatographically on silica using a mixture of dichloromethane/methanol (70:1) and obtained N-(6-methyl-1H-indol-3-ylmethyl)-ndimethylacetamide in the form of a colorless foam material (0.15 g). MS: 203,1 ([M+H]+).

10.4. Using a common methodology With 2-methyl-2-vinylcyclopentane-1,3-dione (publication 1) was introduced into the reaction with benzaldehyde and N-(6-methyl-1H-indol-3-ylmethyl)-ndimethylacetamide and received N-{2-[(2-hydroxy-3-methyl-4-oxo-3-phenylcinnamic-1-enyl)-phenylmethyl]-6-methyl-1H-indol-3-ylmethyl}-ndimethylacetamide in the form of a pale red solid. MS: 463,4 ([M-H]-).

Example 11

3-Hydroxy-4-methyl-2-[(3-methyl-1H-indol-2-yl)-phenylmethyl]-4-p-taillecavat-2-Aenon

Used the eating of a common methodology With 2-methyl-2-p-taillecavat-1,3-dione (from example 4.1) were introduced in the reaction with benzaldehyde and 3-methyl-1H-indole was obtained the desired compound as a colourless solid. MS: 406,6 ([M-H]-).

Example 12

2-[(3,5-Dimethyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-p-taillecavat-2-Aenon

Using a common methodology With 2-methyl-2-p-taillecavat-1,3-dione (from example 4.1) were introduced in the reaction with benzaldehyde and 3,5-dimethyl-1H-indole (publication 3) and obtained the desired compound as a colourless solid. MS: 420,5 ([M-H]-).

Example 13

2-[(3,6-Dimethyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-p-taillecavat-2-Aenon

Using a common methodology With 2-methyl-2-p-taillecavat-1,3-dione (from example 4.1) were introduced in the reaction with benzaldehyde and 3,6-dimethyl-1H-indole (publication 4) and obtained the desired compound as a colourless solid. MS: 420,5 ([M-H]-).

Example 14

2-[(5-fluoro-3-methyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-p-taillecavat-2-Aenon

Using a common methodology With 2-methyl-2-p-tolylsilane-1,3-dione (from example 4.1) were introduced in the reaction with benzaldehyde and 5-fluoro-3-methyl-1H-indole was obtained the desired compound as a red solid. MS: 424,5 ([M-H]-).

Example 15

N-{2-[(2-Hydroxy-3-methyl-4-oxo-3-p-taillecavat-1-enyl)-phenylmethyl]-1H-indol-3-ylmethyl}-ndimethylacetamide

Using the General technique is 2-methyl-2-p-taillecavat-1,3-dione (from example 4.1) were introduced in the reaction with benzaldehyde and N-(1H-indol-3-ylmethyl)-ndimethylacetamide (publication 6) and obtained the desired compound in the form of an almost white solid. MS: 463,4 ([M-H]-).

Example 16

N-{6-Chloro-2-[(2-hydroxy-3-methyl-4-oxo-3-p-taillecavat-1-enyl)-phenylmethyl]-1H-indol-3-ylmethyl}-ndimethylacetamide

Using a common methodology With 2-methyl-2-p-taillecavat-1,3-dione (from example 4.1) were introduced in the reaction with benzaldehyde and N-(6-chloro-1H-indol-3-ylmethyl)-ndimethylacetamide (received from n-(6-chloro-1H-indol-3-yl)-methylamine by acylation in accordance with example 1.2) and obtained the desired compound in the form of an almost white solid. MS: 497,3 ([M-H]-).

Example 17

N-{2-[(2-Hydroxy-3-methyl-4-oxo-3-p-taillecavat-1-enyl)-phenylmethyl]-7-methyl-1H-indol-3-ylmethyl}-ndimethylacetamide

Using a common methodology With 2-methyl-2-p-taillecavat-1,3-dione (from example 4.1) were introduced in the reaction with benzaldehyde and N-(7-methyl-1H-indol-3-ylmethyl)-ndimethylacetamide (received 7-methyl-1H-indole-3-carbaldehyde in accordance with examples 10.1-10.3) and got the desired compound in the form of an almost white solid. MS: 477,4 ([M-H]-).

Example 18

N-{2-[(2-Hydroxy-3-methyl-4-oxo-3-p-taillecavat-1-enyl)-phenylmethyl]-6-methyl-1H-indol-3-ylmethyl}-ndimethylacetamide

Using a common methodology With 2-methyl-2-p-taillecavat-1,3-dione (from example 4.1) were introduced in the reaction with benzaldehyde and N-(6-methyl-1H-indol-3-ylmethyl)-ndimethylacetamide (example 10.3) and what was alocale the desired compound as a pale red solid. MS: 477,3 ([M-H]-).

Example 19

N-{2-[(2-Hydroxy-3-methyl-4-oxo-3-p-taillecavat-1-enyl)-phenylmethyl]-6-methyl-1H-indol-3-ylmethyl}-N-methylformamide

19.1. To a suspension of 6-methyl-1H-indole-3-carbaldehyde (0.96 g, publication 5) in methanol (15 ml) at 22°C was added acetic acid (1.7 ml) and a solution of methylamine in tetrahydrofuran (2 M, 12.0 ml). After stirring for 1 h in 5 portions were added cyanoborohydride sodium (0,76 g) and stirring was continued for 2 hours the Mixture is evaporated and the residue was subjected to distribution between aqueous hydrochloric acid (1 BC) and dichloromethane. Using sodium hydroxide, the pH value of the aqueous layer was brought to 14, and then the aqueous layer was extracted with dichloromethane. The organic layer was dried and evaporated and obtained crude methyl-(6-methyl-1 H-indole-3-ylmethyl)-amine.

19.2. To a solution of crude methyl-(6-methyl-1H-indol-3-ylmethyl)-amine (87 mg) in acetonitrile (1 ml) were added diisopropylethylamine (0.25 ml) and 4-nitrophenylphosphate (90 mg) and stirring was continued for 3 hours the Mixture was diluted with methanol and acetic acid is evaporated and the residue was chromatographically on silica using a mixture of n-heptane/AcOEt (1:1) and obtained N-methyl-N-(6-methyl-1 H-indole-3-ylmethyl)-formamid in the form of a colorless oil. MS: 202,9 ([M]+).

19.3. Using General metodiki 2-methyl-2-p-taillecavat-1,3-dione (from example 4,1) were introduced in the reaction with benzaldehyde and N-methyl-N-(6-methyl-1H-indol-3-ylmethyl)-formamide and got the desired compound as a red solid. MS: 476,6 ([M-H]-).

Example 20

3-Hydroxy-4-methyl-2-(naphthalene-2-alpenlite)-4-phenylcinnamic-2-Aenon

20.1. Using General method 2 does not depend introduced into the reaction with benzaldehyde and got naphthalene-2-ilfenomeno in the form of a colorless solid.

20.2. Using General method D, 2-methyl-2-vinylcyclopentane-1,3-dione (publication 1) was introduced into the reaction with naphthalene-2-infinistream and got the desired compound as a colourless solid. MS: TO 389.5 ([M-H]-).

Example 21

3-Hydroxy-2-[(6-methoxynaphthalene-2-yl)-phenylmethyl]-4-methyl-4-phenylcinnamic-2-snon

21.1 using General method B, 2-bromo-6-methoxynaphthalene was introduced in the reaction with benzaldehyde and received (6-methoxynaphthalene-2-yl)-phenylmethanol in the form of a colorless solid.

21.2. Using General method D, 2-methyl-2-finallyclause-1,3-dione (publication 1) was introduced into the reaction with (6-methoxynaphthalene-2-yl)-phenylmethanone and got the desired compound as a colourless solid. MS: 419,3 ([M-H]-).

Example 22

2-(Benzo[b]thiophene-2-alpenlite)-3-hydroxy-4-methyl-4-phenylcinnamic-2-Aenon

22.1. Using a common methodology In benzo[b]thiophene was introduced in the reaction with benzaldehyde and got benzo[b]thiophen-ilfenomeno in the form of a colorless solid. MS: 223,1 ([M+H-H2On]+).

22.2. Using General method D, 2-methyl-2-vinylcyclopentane-1,3-dione (publication 1) was introduced into the reaction with Enzo[b]thiophene-2-infinistream and got the desired compound as a colourless solid. MS: 395,3 ([M-H]-).

Example 23

2-[(3,5-Dimethylbenzo[b]thiophene-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-phenylcinnamic-2-Aenon

23.1. Using a common methodology 3.5-dimethylbenzo[b]thiophene was introduced in the reaction with benzaldehyde and received (3,5-dimethylbenzo[b]thiophene-2-yl)-phenylmethanol in the form of a colorless oil. MS: 251,4 ([M+H-H2About+).

23.2. Using General method D, 2-methyl-2-vinylcyclopentane-1,3-dione (publication 1) was introduced into the reaction with (3,5-dimethylbenzo[b]thiophene-2-yl)-phenylmethanone and got the desired compound as a colourless solid. MS: 423,5 ([M-H]-).

Example 24

3-Hydroxy-4-methyl-2-[(3-methylbenzo[b]thiophene-2-yl)-phenylmethyl]-4-phenylcinnamic-2-Aenon

24.1. Using General method a 3-methylbenzo[b]thiophene was introduced in the reaction with benzaldehyde and received (3 methylbenzo[b]thiophene-2-yl)-phenylmethanol in the form of a pale yellow solid. MS: 236,8 ([M+H-H2O]+).

24.2. Using General method D, 2-methyl-2-vinylcyclopentane-1,3-dione (publication 1) was introduced into the reaction with (3-methylbenzo[]thiophene-2-yl)-phenylmethanone and got the desired compound as a colourless solid. MS: 409,5 ([M-H]-).

Example 25

2-[(5-fluoro-3-methylbenzo[B]thiophene-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-phenylcinnamic-2-Aenon

25.1. Using General method 5-fluoro-3-methylbenzo[b]thiophene was introduced in the reaction with benzaldehyde and received (5-fluoro-3-methylbenzo[b]thiophene-2-yl)-phenylmethanol in the form of a pale yellow oil. MS: 255,3 ([M+H-H2On]+).

25.2. Using General method D, 2-methyl-2-vinylcyclopentane-1,3-dione (publication 1) was injected to react with (5-fluoro-3-methylbenzo[b]thiophene-2-yl)-phenylmethanone and got the desired compound as a colourless solid. MS: 427,5 ([M-H]-).

Example 26

3-Hydroxy-4-methyl-2-[(5-methylbenzo[b]thiophene-2-yl)-phenylmethyl]-4-phenylcinnamic-2-Aenon

26.1. Using General method 5-methylbenzo[b]thiophene was introduced in the reaction with benzaldehyde and received (5-methylene[b]thiophene-2-yl)-phenylmethanol in the form of a colorless solid. MS: 237,1 ([M+H-H2O]+).

26.2. Using General method D, 2-methyl-2-phenylcyclohexane-1,3-dione (publication 1) was injected to react with (5-methylbenzo[b]thiophene-2-yl)-phenylmethanol and got the desired compound as a colourless solid. MS: 409,3 ([M-H]-).

Example 27

3-Hydroxy-4-methyl-2-[(6-methylbenzo[b]thiophene-2-yl)-phenylmethyl]-4-phenylcinnamic-2-Aenon

27.1. Using General method a 6-methylbenzo[b]thiophene was introduced in the reaction with benzaldehyde and received (6 methylbenzo[b]thiophene-2-yl)-phenylmethanol as an almost white solid. MS: EUR 236.9 ([M+H-H2On]+).

27.2. Using General method D, 2-methyl-2-vinylcyclopentane-1,3-dione (publication 1) was introduced into the reaction with (6 methylbenzo[b]thiophene-2-yl)-phenylmethanone and got the desired compound in the form of a pale yellow solid. MS: 409,3 ([M-H]-).

Example

Tablets, film-coated, containing the following ingredients can be manufactured in the usual manner:

IngredientsIn pill
Engine:
The compound of formula (1)10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
Hydrated lactose60,0 mg70.0 mg
Povidone K3012.5 mg15,0 mg
Sodium salt of starch glycolate12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
(The mass of the nucleus)120,0 mg350,0 mg
Film coating:
Hydroxypropylmethylcellulose3.5 mg7,0 mg
Propylene glycol 60000.8 mg1.6 mg
Talc1.3 mg2.6 mg
Iron oxide (yellow)0.8 mg1.6 mg
Titanium dioxide0.8 mg1.6 mg

The active ingredient is sifted and mixed with microcrystalline cellulose and the mixture granularit with a solution of polyvinylpyrrolidone in water. The granulate is mixed with the sodium salt starch glycolate and magnesium stearate and pressed and get the kernel weight of 120 or 350 mg, respectively. On kernel put a layer of varnish using in the aqueous solution/suspension of the above material, intended for film coating.

The example In

Capsules containing the following ingredients can be manufactured in the usual manner:

IngredientsIn capsule
The compound of formula (I)25.0 mg
Lactose150,0 mg
Corn starch20.0 mg
Talc5.0 mg

The ingredients are sieved and mixed and placed into capsules of size 2.

The example

Solutions for injections may have the following composition:

The compound of formula (I)3.0 mg
Propylene glycol 400150,0 mg
Acetic acidThe number needed to establish pH 5.0
Water for injectable solutionsto 1.0 ml

The active ingredient dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH value was adjusted to 5.0 with assistance from ssnoi acid. The volume of solution was adjusted to 1.0 ml by adding the remaining amount of water. The solution is filtered, placed in vials with the corresponding excess and sterilized.

Example D

Capsules soft gelatin containing the following components, can be manufactured in the usual manner:

Iron oxide, yellow
The contents of the capsules
The compound of formula (I)5.0 mg
Yellow wax8.0 mg
Gidrirovannoe soybean oil8.0 mg
Partially hydrogenated vegetable oil34,0 mg
Soybean oil110,0 mg
Mass content capsules165,0 mg
Gelatin capsule
Gelatin75,0 mg
Glycerol 85%32,0 mg
The Karion 838.0 mg (dry matter)
Titanium dioxide0.4 mg
1.1 mg

The active ingredient is dissolved in warm melt other components and the mixture is placed in the soft gelatin capsules of suitable size. Filled capsules soft gelatin treated by the usual methods.

Example F

The bags containing the following components, can be manufactured in the usual manner:

The compound of formula (1)50.0 mg
Lactose, fine powder1015,0 mg
Microcrystalline cellulose (AVICEL PH 102)1400,0 mg
Sodium salt of carboxymethylcellulose14,0 mg
Polyvinylpyrrolidone K 3010.0 mg
Magnesium stearate10.0 mg
Flavorings1.0 mg

The active ingredient is mixed with lactose, microcrystalline cellulose and sodium salt of carboxymethylcellulose and granularit with a solution of polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and taste the additives and placed in bags.

1. The compounds of formula (I)

in which
means,or
R1denotes hydrogen, C1-C6-alkyl or
-R NR'r", -(C0-C6-alkylen)-R NR'r"where R' and R" are independently selected from the group comprising hydrogen, C1-C6-alkyl, formyl, C1-C6-alkylsulphonyl;
R2, R2'and R2"independently represent hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxygroup;
R3denotes phenyl;
R4denotes hydrogen, C1-C6-alkyl, optionally substituted phenyl or phenyl-C1-C6-alkyl;
R5denotes hydrogen or C1-C6-alkyl;
and pharmaceutically acceptable salts;
where, if not given another definition,
the term "optionally substituted phenyl" means respectively a phenyl, optionally containing one or more substituents independently selected from the group comprising halogen, a nitro-group, a cyano, an amino group, With1-C6-alkyl, hydroxy-group, C1-C6-alkoxygroup and mono - or di-C1-C6-the alkyl substituted amino group.

2. Compounds according to claim 1, in which
means

3. Compounds according to claim 1, in which R1represents C1-C6-alkyl, -(C2-C6-alkylen)-R NR'r"where R' and R" are independently selected from the group comprising hydrogen, formyl and acetyl.

4. Compounds according to claim 3 in which R1refers to 2-amino-ethyl, 2-acetylaminophenol, 2-(N-formyl-N-methylamino)ethyl, 2-acetylamino-2,2-dimethylethyl, methyl or isopropyl.

5. Compounds according to claim 4, in which R1denotes methyl, 2-acetylaminophenol, 2-acetylamino-2,2-dimethylethyl or 2-(N-formyl-N-methylamino)ethyl.

6. Compounds according to claim 5, in which R2, R2'and R2"independently represent hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxygroup.

7. Compounds according to claim 6, in which two of R2, R2'and R2"denote hydrogen and the third one denotes hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxygroup.

8. Compounds according to claim 7, in which two of R2, R2'and R2"denote hydrogen and the third one denotes hydrogen, chlorine, fluorine, methyl, ethyl or methoxy group.

9. Connection of claim 8, in which two of R2, R2'and R2"denote hydrogen and the third one denotes hydrogen, fluorine or methyl.

10. Compounds according to claim 1, in which
R4represents C1-C6-alkyl, optionally substituted phenyl or phenyl-C1-C6-alkyl, and
R5stands With1 -C6-alkyl.

11. Connection of claim 10, in which
R4denotes phenyl or 4-were, and
R5denotes methyl.

12. Compounds according to claim 1, which represent
N-(2-{2-[(2-hydroxy-3-methyl-4-oxo-3-phenylcinnamic-1-enyl)-phenylmethyl]-6-methyl-1H-indol-3-yl}-1,1-dimethylethyl)-ndimethylacetamide,
3-hydroxy-4-methyl-2-[(3-methyl-1H-indol-2-yl)-phenylmethyl]-4-phenylcinnamic-2-Aenon
2-[(3,5-dimethyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-phenylcinnamic-2-Aenon
2-[(3,6-dimethyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-phenylcinnamic-2-Aenon
2-[(5-fluoro-3-methyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-phenylcinnamic-2-Aenon
N-{2-[(2-hydroxy-3-methyl-4-oxo-3-phenylcinnamic-1-enyl)-phenylmethyl]-6-methyl-1H-indol-3-ylmethyl}-ndimethylacetamide,
3-hydroxy-4-methyl-2-[(3-methyl-1H-indol-2-yl)-phenylmethyl]-4-p-taillecavat-2-Aenon
2-[(3,5-dimethyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-p-taillecavat-2-Aenon
2-[(3,6-dimethyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-p-taillecavat-2-Aenon
2-[(5-fluoro-3-methyl-1H-indol-2-yl)-phenylmethyl]-3-hydroxy-4-methyl-4-p-taillecavat-2-Aenon
N-{2-[(2-hydroxy-3-methyl-4-oxo-3-p-taillecavat-1-enyl)-phenylmethyl]-6-methyl-1H-indol-3-ylmethyl}-ndimethylacetamide or
N-{2-[(2-hydroxy-3-methyl-4-oxo-3-p-taillecavat-1-enyl)-phenylmethyl]-6-methyl-1H-indol-3-ylmethyl}-N-methylformamide.

13. Pharmaceutical compositions comprising the compound, oblad the abuser activity of chymase inhibitors according to claim 1 and a pharmaceutically acceptable filler.

14. Compounds according to claim 1, intended for use as therapeutically active substances with the activity of chymase inhibitors.

15. Compounds according to claim 1, intended for use as therapeutically active substances for the treatment and/or prevention of atherothrombosis or asthma.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula or pharmaceutically acceptable salt thereof, where each of W1 and W2 independently denotes CH; X denotes NR5 or CR6R7, where R5 is hydrogen, C1-8alkyl, and each of R6 and R7 is independently hydrogen; Y denotes -(CR8R9)n-, where each of R8 and R9 independently denotes hydrogen or C1-8alkyl, and n is a number from 1 to 4; or X and Y together form -CR10=CR11-, where each of R10 and R11 independently denotes hydrogen; Z is carboxyl; G denotes O, S or CR12R13, where each of R12 and R13 independently denotes hydrogen; A denotes a 5-member heterocyclic ring selected from a group consisting of thiazole, oxazole and thiophene, in which the heterocyclic ring is optionally substituted with C1-8alkyl; B denotes a C1-8alkylene or C2-8alkenylene chain; each of R1 and R2 independently denotes hydrogen, C1-8alkyl, halogen, C1-8alkyl substituted with halogen, or hydroxyl; each of R3 and R4 independently denotes hydrogen or C1-8alkyl; and m is equal to 0.

EFFECT: compounds of formula (I) act as peroxisome proliferator-activated receptor δ activators.

23 cl, 39 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: invention relates to compounds which have general structural formula (C2) or (C5) or (C6) or (D2) or (D5) or (D6)

, and also describes cosmetic and pharmaceutical compositions, containing them.

EFFECT: compositions, containing described compounds can be applied for modulation in vitro and in vivo of binding processes with mediation of binding E-, P- or L-selectin.

8 cl, 814 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: inventive subject matter is compouns and their pharmaceutically acceptable salts which can be applied in prevention and treatment of diseases caused by HCV infection. Structural formulae of the compounds are presented in the claim.

EFFECT: obtaining anti-HCV medicine including the claimed compound or its pharmaceutically acceptable salt as active component.

2 cl, 100 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of C-cyclohexylmethylamine of the general formula (I): in their free form or physiologically compatible salts possessing analgesic effect. In the general formula (I) A means hydrogen atom (H) or unsubstituted phenyl; R1 means saturated or unsaturated, branched or linear mono- or multisubstituted or unsubstituted (C1-C10)-alkyl or (C3-C10)-cycloalkyl, phenyl, naphthyl, furyl, thiophenyl or naphthyl added through unsaturated (C2-C3)-alkyl either through (C1-C3)-alkylene or ethynyl, (C3-C10)-cycloalkyl added through unsaturated (C2-C3)-alkyl or through (C1-C3)-alkylene or ethynyl, or thiophenyl added through unsaturated (C2-C3)-alkyl, either through (C1-C3)-alkylene or ethynyl, respectively, unsubstituted or mono- either multi-substituted with residues chosen independently of one another from a group comprising fluorine (F), chlorine (Cl), bromine (Br), iodine (J) atom, -OR18, -SR18, silyl, unsubstituted or mono- either multi-substituted alkyl wherein substituted of substitutes of (C1-C10)-alkyl are similar or different and are chosen from the group comprising F, Cl, and Br and wherein R18 represents H or saturated or unsaturated, branched or linear, unsubstituted (C1-C10)-alkyl; R2 and R3 mean independently of one another branches or linear saturated unsubstituted (C1-C10)-alkyl, or R2 and R3 form in common the group -CH2CH2NR6CH2CH2 wherein R6 means branched or linear (C1-C10)-alkyl; X in the formula (I) in correspondence with the subformula (1a): of the formula (I) represents or wherein B represents -OH, -OR7, H, F or Cl wherein R7 means mono- or multi-substituted phenyl added through (C1-C3)-alkylene wherein substitutes of phenyl are chosen from F and Cl and others. Also, invention relates to a pharmaceutical composition based on compounds of the invention and to using these compounds. Proposed compounds can be used in treatment of pain being firstly in case of nephropathic or chronic pains.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 421 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to compounds of formula I ,

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

EFFECT: higher efficiency.

13 cl, 18 ex, 1 tbl

The invention relates to derivatives of 5-areolation formula I, where a represents-CH2-, -C(O)- or-S(O)2-; Z denotes a group of formula b or D:

< / BR>
where X is O or S; R6and R7independently from each other selected from the group including hydrogen, C1-C6alkyl, CF3WITH1-C6alkylthio,1-C6alkoxy, halogen, nitro, hydroxy, and-NR9R10where R9and R10independently of one another denote hydrogen or C1-C6alkyl; R1means hydrogen, C1-C6alkyl, C1-C6alkoxy, hydroxy2-C6alkyloxy, hydroxy, halogen, cyano, carboxy, co2SOP(CH3)2, -СОNR9R10, -ОСОNR9R10or ОSO2R11where R9and R10have the meanings indicated above, and R11means1-C6alkyl or CF3; R3means-SO2R12or-SO2NR13R14where R12means1-C6alkyl; R13means hydrogen or C1-C6alkyl, and R14means hydrogen, C1-C6alkyl, C3-C6cycloalkyl,2-C6alkenyl, hydroxy SS1-C6alkyl, benzyl, phenethyl, naphtalate, acyl, morpholino-C1-C6alkyl, pyrrolidino-C1-C6alkyl, pyridyl-C1-C6alkyl, furanyl-C1-C6alkyl, or R13and R14together with the nitrogen atom to which they are attached, optionally form heterocyclization selected from piperidino, morpholino, di-(C1-C6alkyl)morpholino, pyrrolidino, methylpiperazine, phenylpiperazine, forfilipino; and their pharmaceutically acceptable salts or their esters or carbamates, individual isomers and mixtures of isomers and method thereof

The invention relates to the use of compounds of the type of retinoids as active agents in cosmetic compositions or pharmaceutical compositions intended for the treatment of disorders or diseases associated with sverrehelena receptors PPK and/or hypervitaminosis A

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining derivatives of 2-aryl(hetaryl)-1H-indoles of general formula I:

IndexR1R2IaClIbОСН3IcHIdHIeНIfClIgCl

which is characterised by the fact that derivatives of 4-(1H-indol-3-yl)-but-3-en-2-ons II and phenylhydrazine hydrochloride are boiled in dimethylformamide for 2 min. Method ensures obtaining target products with output to 83%.

EFFECT: compounds can be used for synthesis of novel preparations of pharmaceutical purpose.

2 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel 4-(1H-indol-3-yl)-but-3-en-2-one derivatives of general formula 3: , : which can be used in synthesis of novel preparations for pharmaceutical and agricultural purposes. The method involves mixing 2-alkyl-5-(2-amino-4-alkylphenyl)-furans 1 with aromatic and heteroaromatic aldehydes 2 in acetic acid in equimola ratio at temperature 35°C for 40 minutes in the presence of 0.01 ml hydrochloric acid.

EFFECT: improved method.

2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel indole derivatives, specifically to hydrogen halides of N-[2-(1-alkyl-1H-indol-3-yl)-1-(4-alkylpiperazine-1-carbonyl)-vinyl]-2-fluorobenzamide of formula I: , where R1 and R2=alkyl C1-C6, X=Cl, Br, having local anaesthetic and antiarhythmic activity.

EFFECT: obtaining new indole derivatives having useful biological properties.

11 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described novel acylsulfonamide peri-substituted condensed bicyclic compounds of general formula (I), values of radicals are given in invention formula. Also described is pharmaceutical composition based on formula (I) compound.

EFFECT: compounds can be used for inhibition of prostaglandin E2 binding with receptor EP3.

30 cl, 371 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I , where X is N or CH; R1 is -C(O)-NR8R9 or -C(O)-OR10, and R2 is hydrogen; or alternatively R2 is and R1 is hydrogen or halogen; Y is N or CH; R3, R4, R5 and R6 are independently selected from a group consisting of hydrogen, halogen, (lower)alkoxy, (lower)fluoroalkyl, (lower)fluoroalkoxy and (lower)fluoroalkylsulfanyl; or R3 and R4 together with carbon atoms with which they are bonded form a 6-member unsaturated ring which can contain one nitrogen heteroatom; R7 is hydrogen or (lower)alkyl; R8 is hydrogen or NH2; R9 is selected from a group consisting of (lower)alkyl, (lower)alkenyl, (lower)alkoxyalkyl, -(CH2)m-(C3-C7)cycloalkyl, -(CH2)m-piperidinyl, -(CH2)m-phenyl, where the phenyl ring is unsubstituted or substituted with one or two groups selected from halogen, (lower)alkoxy, (lower)fluoroalkyl and (lower)fluoroalkoxy, -(CH2)m-naphthyl and pyridylamino; R10 is (lower)alkenyl; R11 is selected from a group consisting of -C(O)-R12, -SO2-R13 and -SO2-NR14R15; R12 is selected from a group consisting of (lower)alkyl, (lower)alkoxyalkyl, -(CH2)n-(C3-C7)-cycloalkyl, -(CH2)n-phenyl and -(CH2)n-pyridyl, where phenyl or pyridyl are unsubstituted or substituted with one (lower)alkyl; R13 is selected from (lower)alkyl or -(CH2)n-phenyl, where phenyl is unsubstituted or substituted with one (lower)alkyl; R14 is (lower)alkyl; R15 is (lower)alkyl; m equals 0, 1 or 2; n equals 0 or 1; and all their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: novel indole and benzimidazole derivatives which have modulating effect on the CB1 receptor are obtained.

26 cl, 3 tbl, 148 ex

FIELD: chemistry; pharmaceutics.

SUBSTANCE: present invention relates to novel cyclohexane derivatives of formula (I) or their pharmaceutically acceptable salts having inhibitory effect on Na+-glucose cotranspoter (SGLT2), as well as to pharmaceutical compositions based on the said compounds and their use in preventing or treating diabetes, diabetic complications caused by hyperglycaemia or obesity. , where A is -O-; n is an equal to 0 or 1; R6 and R7 each independently represents a hydrogen atom or a C1-C6alkyl group, m is an integer selected from 1-3; Q is selected from Q1 - Q5, given in formula 2.

EFFECT: obtaining novel cyclohexane derivatives or their pharmaceutically acceptable salts and preparation of a pharmaceutical composition based on the said compounds.

15 cl, 19 dwg, 11 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: novel compound is N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or its pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with CFTR activity modulation properties.

2 cl, 485 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of new complexing analytical reagents which are suitable for doping nanoparticles and for use in luminescence-spectral analysis, biochip technology, as well as extractants of ions of heavy and rare-earth metals. Description is given of complexing benzo-containing heterocyclic compounds, which contain a β-dicarbonyl substitute with fluorinated radicals of formula: HetAr-C(O)CH2C(O)CF3, where HetAr= ,

which form luminescent complexes with Eu3+ ions. Proposed compounds are on the same level as compounds with closely resembling structure with regards to duration of luminescence and bonding efficiency, although they are easily accessible with respect technology of production and have high water solubility >10-4 mol/l, which enables their use in making conceptually new biochips with time, spatial and spectral signal selection.

EFFECT: high output of desired product.

1 cl, 5 dwg, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I) compounds and to their use in treating diseases related to lipid storage disorders, such as atherosclerosis and diabetes. In R1 represents hydrogen, alkyl, halogen, formyl, hydroxyalkyl or trifluoromethyl, R2 represents hydrogen, alkyl or halogen, R3 represents hydrogen or alkyl, R4 represents hydrogen, alkyl, hydroxy or alkoxy, R5 and R6 are chosen from hydrogen, alkyl, phenylalkyl, hydroxyalkyl, alkoxycarbonyl and phenyl, A represents aryl or heterocyclyl, m equals 0-3, n equals 0-1, p equals 0-3, sum of m, n and p equals 1-4, the bond between carbon atoms Ca and Cb is a single or double carbon-carbon bond.

EFFECT: obtaining new biologically active compounds.

27 cl, 147 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and concerns an agent for myocardial infraction containing an antibody which identifies IL-6 receptor as an active ingredient.

EFFECT: invention provides improved state of an affected zone in myocardial infraction and inhibited left ventricular remodelling following myocardial infraction.

23 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and concerns a pharmaceutical combined composition for treating and preventing hypertension in patients with diabetes, ventricular hypertrophy in patients with diabetes for the purpose of delay of progression of diabetic renal diseases or for the purpose of reduction of proteinuria in patients with diabetes, containing the AT1-antagonist valsartan or its pharmaceutically acceptable salt and calcium canal blocker which is presented by amlodipine benzylate, and a pharmaceutically acceptable carrier.

EFFECT: preparing the pharmaceutical combined composition for treating or preventing hypertension.

3 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and may be used for treating patients with hypertension and lipid storage disease. There is applied a combined drug containing dihydropyridine, calcium canal blockers, and statin, a hypolipidemic agent. The drug is prepared in such a manner that release rate of said ingredients can be controlled with respect to each other.

EFFECT: method allows higher clinical effectiveness and compliance, prevented antagonist and side effects of the combined therapy.

27 cl, 12 tbl, 10 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: method of therapy of a cardiovascular pathology involves laboratory assay of a number of blood circulating membrane microparticles, with additionally prescribed Preductal MB 0.35 1 tablet × twice a day with underlying basic therapy or as independent therapy: the number of membrane microparticles exceeding 40 in 4 cm2 of a slide - for 1 month that is followed by another blood sampling for the content of microparticles and making a decision on the further therapeutic approach involving Preductal; the normalised values - the therapeutic course is continued for 3 months; the preserved high values of the content of the membrane microparticles - the therapeutic course is continued for 6 months under laboratory control of the content of microparticles.

EFFECT: reduced number of blood circulating membrane microparticles creates a protective effect on vascular endothelium, prevents the development or the progression of endothelial dysfunction, reduces a risk of the onset and the progression of the cardiovascular diseases.

4 ex, 3 dwg

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