Derivatives of benzo(b)thiepin-1,1-dioxides, the retrieval method, the drug and its production method

 

The invention relates to substituted derivatives of benzo (b) thiepin-1,1-dioxides and their additive salts with acids of the formula I, in which R1is methyl, ethyl, propyl, butyl; R2- H, HE; R3a balance of amino acids, the remainder of diaminoanisole, and the balance of amino acids, the remainder of diaminoanisole in case you need one - or multi-substituted aminoadenine group; R4is methyl, ethyl, propyl, butyl; R5is methyl, ethyl, propyl, butyl; Z is a covalent bond. Also described is a method of obtaining compounds, drug based on them and the way to obtain medicines. The compounds can be used as lipid-lowering means. 4 S. and 2 C.p. f-crystals, 2 PL.

The invention relates to substituted derivatives of benzo(b)thiepin-1,1-dioxides, their physiologically acceptable salts and physiologically functional derivatives.

Described derivatives of benzo(b)thiepin-1,1-dioxides, as well as their use for the treatment of hyperlipidemia and atherosclerosis and hypercholesterinemia [application PCT/US 97/04076, publication WO 97/33882].

The aim of the present invention are other compounds that terapeuticas compared to the described in the prior art compounds already in low doses cause increased fecal secretion of bile acids. Particularly desirable was the reduction of the effective dose (ED200at least 5 times compared to the one described in the prior art compounds.

This invention thus relates to compounds of formula I,where R1is methyl, ethyl, propyl, butyl; R2- N., HE, NH2, NH-(C1-C6)-alkyl); R3a balance of amino acids, the remainder of diaminoanisole, the rest of trainability, the rest of terminability, and the balance of amino acids, the remainder of diaminoanisole, the rest of criminality or the rest of terminability in case you need one - or multi-substituted aminoadenine group.

R4is methyl, ethyl, propyl, butyl; R5is methyl, ethyl, propyl, butyl; Z Is -(C= 0)n-C0-C16-alkyl-, -(C= O)n-C0-C16-alkyl-NH-, -(C= O)n-C0-C16-alkyl-O-, -(C=O)n-C1-C16-alkyl-(C=O)m, covalent bond; n is 0 or 1; m is 0 or 1;
and their pharmaceutically acceptable salts and physiologically functional derivatives.

Preferred are the compounds of formula I in which one or more residues have the following meanings:
R1is ethyl, propyl, butyl;
R2- N., HE, NH2, NH-(R4is methyl, ethyl, propyl, butyl;
R5is methyl, ethyl, propyl, butyl;
Z is -(C= O)n-C0-C16-alkyl-, -(C= O)n-C0-C16-alkyl-NH-, -(C= O)n-C0-C16-alkyl-O-, -(C=O)n-C1-C16-alkyl-(C=O)m, covalent bond;
n is 0 or 1;
m is 0 or 1;
and their pharmaceutically acceptable salts.

Especially preferred are the compounds of formula I in which one or more residues have the following meanings:
R1- ethyl, butyl;
R2- HE;
R3- the rest of diaminoanisole, and the rest of diaminoanisole in case you need one - or multi-substituted aminoadenine group;
R4is methyl;
R5is methyl;
Z is -(C=O)n-C1-C4-alkyl-, a covalent bond;
and their pharmaceutically acceptable salts.

Pharmaceutically acceptable salts due to their higher solubility in water as compared with the initial or basic compounds are particularly suitable for medical applications. These salts must contain a pharmaceutically acceptable anion or cation. Pharmaceutically acceptable additive salts of acids of the proposed compounds are salts of inorganic acids, such as Sol and organic acids, as, for example, acetic acid, benzolsulfonat, benzoic, citric, econsultancy, fumaric, gluconic, glycolic, sotynova, lactic, lactobionic, maleic, malic, methansulfonate, amber, pair-toluensulfonate, wine and triperoxonane acid. For medical purposes especially preferred are the salts of hydrochloric acid. Pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), and salts of alkaline earth metals (such as magnesium salts and calcium).

Salts with a pharmaceutically unacceptable anion likewise covered by the invention as a necessary intermediate products to obtain or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic purposes, for example for use in vitro.

Used here, the term "physiologically functional derivative" refers to any physiologically acceptable derivative of the proposed connection, for example an ester, which when administered to a mammal, such as man, are able to form (directly or indirectly) such a compound or its active metabolite.

An additional aspect of this IP vivo to compounds according to the invention. Such prodrugs may themselves be or not to be active.

Compounds according to the invention can exist in different polymorphic forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the proposed compounds related to this invention and are a further aspect of the present invention.

Hereinafter all references to "compound(s) according to formula (I)" refer to compound(s) of formula (I) as described above, and their salts, solvate and physiologically functional derivatives.

The number of compounds according to formula (I), which is required to achieve the desired biological effect depends on a number of factors, such as the selected specific connections, the intended route of administration and the clinical condition of the patient. Mostly daily doses are in the range from 0.1 to 100 mg (typically from 0.1 to 50 mg) per day per kilogram of body weight, for example, 0.1 to 10 mg/kg/day. Tablets or capsules may contain, for example, from 0.01 to 100 mg, typically from 0.02 to 50 mg. In the case of pharmaceutically acceptable salts are given the weight values include the weight liberated from the salt ion benzo(b)tiepin. For the prevention or therapy called you is respectfully they are presented with a suitable carrier in the form of pharmaceutical compositions. Of course, the media must be suitable, i.e. it is compatible with other ingredients of the composition and harmless to the health of the patient. The carrier may be solid or liquid, or both, and preferably prepared together with the connection in the form of individual doses, for example in the form of a tablet, which may contain from 0.05 to 95 wt.% the active substance. Also there may be other pharmaceutically active agents, including other compounds according to formula (I). The pharmaceutical compositions according to the invention can be obtained by one of the known pharmaceutical methods, which mainly consist in the fact that the ingredients are mixed with pharmacologically acceptable carriers and/or auxiliary substances.

The pharmaceutical compositions according to the invention are suitable for oral and peroral (for example sublingual) administration, although the most suitable route of administration in each individual case depends on the type and severity treatable condition and the type of the used compounds according to formula (I). All the drugs in the form of pills and long-acting drugs in the form of pills also belong to the scope of the present invention. Prepact the ku coverings are acetated cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose and anionic polymers of methacrylic acid and methyl ester of methacrylic acid.

Pharmaceutically suitable compounds for oral administration may be presented as separate units, such as capsules, membranes pills, tablets for sucking or tablets, each of which contains a number of compounds according to formula (I); as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquid; or as an emulsion oil-in-water or water-in-oil. Such compositions can, as already mentioned, can be prepared by any suitable pharmaceutical method which includes a step in which the contact of the active substance and the carrier (which may consist of one or more additional ingredients). Typically, the compositions are obtained by uniform and homogeneous mixing of the active substance with a liquid and/or powdered solid carrier, after which the product if necessary mold. So, for example, can be obtained tablet, in which the pressed or molded powder or granules of the compound, if necessary, with one or more additional in as, for example, a powder or granules, if necessary mixed with a binder, which imparts lubricity agent, inert diluent and/or one (several) of surface-active/dispersing means in a suitable equipment. Decorated tablets can be obtained by molding powder, moistened with a liquid inert diluent compounds on suitable equipment.

Pharmaceutical compositions suitable for peroral (sublingual) administration include tablets for sucking, which contain the compound according to formula (I) with a flavoring agent, normally sucrose and gum Arabic or Trianta, and lozenges, which contain the compound in an inert basis such as gelatin and glycerol or sucrose and gum Arabic.

The subject of this invention are hereinafter mixture of isomers of formula I, as well as pure stereoisomers of the formula I, a mixture of diastereoisomers of formula I and the pure diastereomers. Separation of mixtures perform chromatographic method.

Preferred are a racemic mixture, and enantiomerically pure compounds of formula I of the following structure:


alanine; glycine; and Proline;
cysteine; histidine; glutamine;
aspartic acid, isoleucine; arginine;
glutamic acid; lysine; serine;
phenylalanine; leucine; threonine;
tryptophan; methionine; valine;
tyrosine; asparagine;
2-aminoadenosine acid; 2-aminoadamantane acid;
3-aminoadenosine acid; 3-aminoadamantane acid;
beta-alanine; 2-aminofilina acid;
2-aminobutyric acid; 2,4-diaminopentane acid;
4-aminobutyric acid; desmosine;
piperidino acid; 2,4-diaminopimelic acid;
6-aminocaproic acid; 2,3-diaminopropionic acid;
2-aminoheptanoic acid; N-ethylglycine;
2-(2-thienyl)-glycine; 3-(2-thienyl)-alanine;
penicillamine; sarcosine;
N-ethylasparagine; N-methylisoleucine;
hydroxylysine; 6-N-methyllysine;
Hello-hydroxylysine; M-methylvaline;
3-hydroxyproline; Norvaline;
4-hydroxyproline; norleucine;
isodesmosine; ornithine;
ALLO-isoleucine;
N-methylglycine.

Abbreviation of the amino acids are in overall conventional methods (Schroeder, Luebke, Nhe Peptides, volume I, New York 1965, p. XXII-XXIII; Houben-Weyl, Methods der Organischen Chemie, volume XV/1 and 2, Stuttgart 1974). Amino acid pGlu means pyroglutamyl, Nal - 3(2-naphthyl)-alanine, Azagly-NH2- connection of the ode are acids and inorganic salts are decomposed by the hydrolysis of amino acids.

Under the remnants of deamination, triaminicol, detremination understand peptides comprising from 2 to 4 of the above mentioned amino acids.

As appropriate aminosidine groups (Greene, "Protective Groups in Organic Synthesis") first used:
Arg(Tos), Arg(Mts), Arg(Mtr), Arg(PMV), Asp(OBzl) - Asp(OBut), Cys(4-MeBzl), Cys (Acm) Cys(SBut), Glu(OBzl), Glu(Obut), His(Tos), His(Fmoc), His(Dnp), His(Trt), Lus(Cl-Z), Lys(Boc), Met(O), Ser(Bzl), Ser(But), Thr(Bzl), Thr(But), Nrp(Mts), Trp(CHO), Tyr(Br-Z), Tyr(Bzl) or Tight(But).

As aminosidine groups preferred ottsepleny when catalytic hydrogenation benzyloxycarbonyl-(Z)-remnant, otsepleniya weak acid 2-(3,5-dimethoxyphenyl)propyl(2)oxycarbonyl(Ddz-) or trically (Trt)-residues, otsepleniya secondary amines 9-fluorenylmethoxycarbonyl (Fmoc).

This invention further relates to a method for obtaining derivatives of benzo(b)thiepin-1,1-dioxides of the formula I:

Method of producing compounds of the formula I, characterized in that the amine of formula II, where R1, R2, R4and R5have shown in the formula I value, is subjected to the interaction with the compound of the formula III, where R3and Z have the meanings given in formula I, with the elimination of water and formation of the compounds of formula I and the compound obtained vosproizvodenie. If the residue R3we are talking about the rest of monoaminoxidase, this residue, if necessary, may be extended by linking with an amine of the formula II sequence until the rest of diaminoanisole, the rest of trainability or balance terminability.

The compounds of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives represent an ideal drug for the treatment of disorders of lipid metabolism, in particular hyperlipidemia. The compounds of formula I are equally suitable to influence the level of serum cholesterol, as well as for the prevention and treatment of atherosclerotic events. These compounds, if necessary, can also be administered with a statin, as, for example, simvastatin, fluvastatin, pravastatin, tseriwastatina, lovastatin or atorvastatin. The following results illustrate the pharmacological activity of the proposed connections.

Biological study of the compounds according to the invention was carried out by removing the ED200. It was studied the effect of the proposed connection on the transport of bile acids in the ileum and fecal secretion of bile acids in rats after oral introduction the time.

1) the composition of the test and reference substances.

For preparation of aqueous solution used the following recipe:
the substance was dissolved in an aqueous solution containing adequate amounts of solutol (= hydroxystearate of polyethylene glycol 600; BASF, Ludwigshafen, Germany; Chargennr. 1763) so that the final concentration solutol in aqueous solution was 5%. The solution/suspension was administered at a dose of 5 ml/kg orally.

2) Conditions of experience
Male Wistar rats (Kastengrund, Hoechst AG, weight 250-350 g) in groups of 6 animals kept for 10 days before testing (day 1) when reversing the rhythm of the day/night (400-1600in the darkness, 1600-400in the light) and were given standard feed mixture (Altromin, Lage, Germany). Three days before the start of the test (day 0) the animals were divided into groups of 4 individuals.

The division of animals in the test groups are shown in table. 1.

3) experiment
After intravenous or subcutaneous injection of 5 microcurie14With-taurocholate the rat (day 0) was given to the media or the test substance in the 700-800and 1500-1600the next day (day 1) (treatment one day). The study of fresh feces to determine14With-taurocholate produced after 24 hours, which was Bandarawela in 100 ml of demineralized water and homogenized (Ultra Turrax, Janke & Kunkel, IKA-Werk). Aliquot part (0.5 g) was weighed and burned at the tip for burning (Combusto Cones, Canberra Packard) in apparatus for burning (Tri Carb(R)307 combuster Canberra Packard GmbH, Frankfurt am main, Germany). Produced14CO2absorb on rb-Sorb(R)(Canberra Packard). Subsequent measurement of radioactivity14C produced after adding the sample scintillator (Perma Fluor complete scintillation coctail 6013187, Packard) using a liquid scintillation counter (Sands). Fecal selection14With human beings need it to acid was calculated as cumulative and/or percentage of residual radioactivity (see below).

4) Observations and measurements
Fecal selection14S-TCA was determined in burnt aliquot parts collected with an interval of 24 hours samples of fresh feces, calculated as the cumulative percentage" of injected activity and expressed as % residual activity (=remaining activity, i.e. entered the activity minus the already selected activity). To calculate the curve dose-activity allocation14With human beings need it to acid expressed as a percentage of the corresponding values for the control group (treated by the media). ED200, i.e. the dose which is kitana by interpolating the sigmoid or linear curve dose-effect. The calculated ED200corresponds to the dose that doubles fecal secretion of bile acids.

5) Results
Table. 2 shows measured values of the ED200selection.

6) Discussion
From these measurements it is necessary that the compounds of formula I compared to the one described in the prior art compounds have superior action 20 times.

The following examples in more detail to explain the invention without limiting it is described in the examples of products and forms of execution.

Example 1


With46H74N6OS (887,20). Mass spectrum (M+N)+=887,5
Comparative examples of PCT/US 97/04076;
Comparative example 1


Comparative example 2


Comparative example 3


Examples or comparative examples were obtained as follows (shown in the synthesis of onlyof diastereomers):
Scheme 1

Synthesis of compound 6 in the form of smashing of oxime and 0.5 ml N similar to synthesis of compound 3. Yield 290 mg (94%) 6a/b in the form of amorphous solids. TLC (ethyl acetate/n-heptane 2: 1) Rfor = 0.6. C50H64N4C8S (881,15), Mass spectrum (M+N)+=881,5.

Synthesis of compound 7 as a mixture of diastereomers:
285 mg (0.32 mmol) of 6a/b was dissolved in 5 ml of DMF. After addition of 0.6 ml of diethylamine kept for 30 minutes. Treatment was performed similarly to the synthesis of compound 3. 173 mg (81%) of 7a/b in the form of amorphous solids. TLC (methylene chloride/methanol 15: 1). Rf=0,2, educt 6a/b Rf=0,4. With35H54N4096(658,91) Mass spectrum (M+N)+=659,4.

Synthesis of compound 8 as a mixture of diastereomers:
168 mg (0.25 mmol 7a/b were subjected to interaction analogous to the synthesis of compounds 6 and 7 and received 169 mg (75% in two stages) 8A/b in the form of amorphous solids. TLC (methylene chloride/methanol 9: 1). Rf=0,3. C46H74N6O9S (887,20). Mass spectrum (M+N)+=887,5.


Claims

1. Derivatives of benzo(b)thiepin-1,1-dioxides of the formula I

where R1is methyl, ethyl, propyl, butyl;
R2- H, HE;
R3a balance of amino acids, the remainder of diaminoanisole, and the balance of amino acids, the remainder of diaminoanisole, if not the>R5is methyl, ethyl, propyl, butyl;
Z is a covalent bond,
and their pharmaceutically acceptable salts.

2. The compounds of formula I on p. 1, wherein one or more residues have the following meaning: R1is ethyl, propyl, butyl; R2- H, HE; R3a balance of amino acids, the remainder of diaminoanisole, and the balance of amino acids, the remainder of diaminoanisole, if necessary, one - or multi-substituted aminoadenine group;
R4is methyl, ethyl, propyl, butyl;
R5is methyl, ethyl, propyl, butyl;
Z is a covalent bond,
and their pharmaceutically acceptable salts.

3. The compounds of formula I under item 1 or 2, characterized in that one or more residues have the following meanings
R1- ethyl, butyl;
R2- HE;
R3- the rest of diaminoanisole, and the rest of diaminoanisole, if necessary, one - or multi-substituted aminoadenine group;
R4is methyl;
R5is methyl;
Z is a covalent bond,
and their pharmaceutically acceptable salts.

Method of producing compounds of the formula I according to one or more paragraphs.1-3, namely, that the amine of formula II

where R1, R2, R4and R5II
where R3and Z have the meanings given in formula I,
with the elimination of water and formation of the compounds of formula I, the compound obtained of the formula I, if necessary, transferred to a physiologically acceptable salt.

5. A drug that promotes the secretion of bile acids containing one or more compounds of one or more paragraphs.1-3.

6. The method of obtaining medicines, characterized in that one or more compounds of one or more paragraphs.1-3 is mixed with a pharmaceutically acceptable carrier and the resulting mixture is adjusted to suitable for introduction form.

 

Same patents:

The invention relates to nitrate ACE-inhibitor of formula I or II, where Y is phenyl, X is C(RIIIRIV, RIII, RIV, RVand RVI- hydrogen containing stoichiometric amount of nitric acid

The invention relates to biotechnology and can be used for Introduzione nucleic acids into cells

The invention relates to benzodiapines General formula I, their derivatives and analogues

The invention relates to a heterocyclic derivative benzocyclobutene General formula I, where R1IT denotes, C1-C6alkoxy; R2represents C1-C6alkyl; R3represents C1-C6alkyl, -(CH2)1-2-aryl, where aryl is phenyl, CH2-(C3-C7) cycloalkyl; R4and R5at the same time or in distinction from each other denote H, Cl, F, C1-C6alkyl, HE, C1-C6alkoxy, -(CH2)0-2-aryl, -O-(CH2)0-2-aryl, April is phenyl, unsubstituted or one-deputizing, -SOP(R6R7)

The invention relates to optically active derivative benzodiapine formula I, where R represents a lower alkyl group; R1and R2independently represent a lower alkyl group or together represent lower alkylene, which has excellent osteoinductive action, it is useful as a prophylactic or therapeutic agent against bone disease

The invention relates to the group's derivative aminomethylpropanol acid represented by the following formula:

< / BR>
where R1represents a hydrogen atom, a lower alkyl group or aracelio group; R2represents a hydrogen atom or a halogen atom; the carbon atom marked with (R) denotes the carbon atom in (R)-configuration; the carbon atom marked with (S) means a carbon atom in (S)-configuration, or their pharmaceutically acceptable salts, pharmaceutical compositions, a stimulating effect on2and3-adrenoceptor, comprising as an active ingredient derived aminomethylpropanol acid, a means to soothe the pain and how calm the pain
The invention relates to medicine, namely to urology, and for the treatment of patients with acute purulent obstructive pyelonephritis in combination with metabolic X-syndrome

The invention relates to new N-phenylamine and N-pyridylamine derivative of the formula I

< / BR>
in which X denotes O or S;

R1and R2which may be identical or different, denote hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl or R1and R2together with the carbon atom to which they are attached, form a (C3-C8)cycloalkyl;

R3means (C6-C12)aryl, optionally substituted by one or more radicals Y, which may be the same or different;

Y represents halogen;

R4and R5represent hydrogen;

Ar denotes one of the following groups or WITH:

< / BR>
T represents hydrogen or (C1-C6)alkyl;

T3and T4which may be identical or different, denote (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)allylthiourea;

R6and R7each denotes hydrogen or R6and R7together represent a bond;

Z denotes either (I) the divalent group-CHR9- in which the R11-, in which R10and R11together they form a bond that Z represents the group-CH=CH-, or R10and R11that may be the same or different, have the meanings indicated above for R9or (III) a divalent group-CHR12-CHR13-CH2-, in which R12and R13together they form a bond, Z represents-CH=CH-CH2-, or R12and R13that may be the same or different, have the meanings indicated above for R9,

as well as their additive salts with pharmaceutically acceptable acids or bases, and method of production thereof, pharmaceutical compositions and drug manifesting gipolipedimecescoe and antiatherosclerotic action based on them

The invention relates to trilateralization formula (I) in which R1 means a hydrogen atom, halogen atom or lower alkyl radical, R2, R3 and R4 independently denote a hydrogen atom or a lower alkyl radical, Az means a nitrogen-containing aromatic N-methylseleninic the five-membered heterocycle containing one to three nitrogen atoms, with analgesic activity

The invention relates to tricyclic condensed heterocyclic compounds of the formula I, X is, for example, CH, CH2, СНR (where R means a lower alkyl group or a substituted lower alkyl group) or CRR' (where R and R' have the values specified above for R); Y means, for example, CH, CH2or C=O; z means, for example, S, S=O=; U denotes C; R1-R4independent means, for example, a hydrogen atom, SR (where R has the above values), phenyl group, substituted phenyl group, follow group, thienyl group, benzofuran or benzothiazyl at least one element of R5and R8means, for example, HE and the rest of the elements of R5and R8independent means, for example, a hydrogen atom; and their optical isomers, conjugates, and pharmaceutically acceptable salts

The invention relates to new indole derivative of the formula I

< / BR>
where R1- H, halogen, CN; R2and R3the same or different is H, C1-C4alkyl, halogen; R4- H, C1-C4alkyl; And means cyanoaniline, aminosulphonylphenyl, aminopyridine, aminopyrimidine, halogenopyrimidines or cianciarulo group, provided that if all R1, R2and R3- N, when both R2and R3- N or when ring A - aminosulphonylphenyl group and both R1and R2the halogen atoms is excluded; and, in addition, when the ring a represents cyanophenyl group, 2-amino-5-pyridyloxy group or 2-halogen-5-pyridyloxy group, and R1represents a cyano or halogen group, at least one of R2and R3must not be a hydrogen atom

The invention relates to new derivatives (tetrahydro-1-oxido-thiopyran-4-yl)phenyloxazolidine General formula I, in which R1means methyl, ethyl, cyclopropyl, dichloromethyl, R2and R3are identical or different and denote hydrogen or fluorine, or their pharmaceutically acceptable salts, and the new derived (tetrahydro-1,1-oxido-thiopyran-4-yl)phenyloxazolidine General formula II in which R2and R3are identical or different and denote hydrogen or fluorine, R4means ethyl or dichloromethyl, or their pharmaceutically acceptable salts

The invention relates to novim retinoid compounds of General formula I, II, III, IV with retinoid negative hormone biological activity and/or activity of antagonist retinoids, compositions based on them, a method of determining the retinoid antagonists hormones,the method of treating a pathological state in a mammal, vospriimchivosti to treatment with retinoid antagonist or negative hormone by injection of compound I or II

The invention relates to new derivatives of balkanov General formula (A)

< / BR>
where Ar is phenyl which may be unsubstituted or substituted one, two or three substituents independently chosen among Cl, Br, F, -OMe, NO2, CF3C1-4lower alkyl, -NMe2, -NEt2, -SCH3, -NHCOCH3; 2-thienyl, 2-furyl; 3-pyridyl; 4-pyridyl or 3-indolyl; R-OCH2R1where R1choose from a number of-CH= CME2The CME=CH2-The CCH; provided that when Ar is a phenyl,4-alkylphenyl, 4-methoxyphenyl or 3,4-acid, R can be any except 3-methyl-2-butenyloxy

The invention relates to benzodiapines General formula I, their derivatives and analogues

The invention relates to 2-(iminomethyl)aminoaniline derivative of General formula I, And where the aromatic residue of the formula Ia, R1and R2independently H, halogen, HE, linear or branched C1-C6alkyl, linear or branched C1-C6alkoxyl, R3-H, linear or branched C1-C6alkyl, or-COR4where R4-C1-C6alkyl or the residue IC, linear or branched C1-C6the five-membered alkyl or a heterocycle containing 1-4 heteroatoms selected from O, S, N, and in particular: thiophene, furan, pyrrole or thiazole, carbon atoms which is unsubstituted or substituted by one or more groups selected from linear or branched C1-C6of alkyl, C1-C6alkoxyl or halogen; X is-CO-N(R3)-X'-, -NH-CO-X'-, -CH=,-CO -, or a bond, and X' represents -(CH2)n- where n = 0-6; Y means Y'-, -Y'-NH-CO-, -CO-Y', Y'-CO-, -N(R3)-Y'-, -Y,-N(R3)-, Y'-CH2-N(R3)-CO-, -Y'-O-, -Y'-O-Y' - or a bond, and Y' is -(CH2)n- where n = 0-6; Неt-pyrrole, pyrrolidine, furan, thiophene, imidazole, imidazoline, oxazole, isoxazol, oxazoline, isoxazole, thiazole, thiazoline, thiazolidine, thiazolidine, azetidine, piperidine, imidazolidine, they

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.

EFFECT: increased choice of cysteine protease inhibitors.

34 cl, 1 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biphenylsulfonylcyanamides of the formula (I): wherein R1 means: 1. (C1-C8)-alkyl; 4. -CnH2n-nn-Y wherein nn = 0 or 2 and n = 0-4, and n is not 0 or 1 if nn = 2; 5. CnH2n-nn-Y wherein nn = 0 or 2 and n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with amino-group or NR(22)R(23); R2 means: 2. (C1-C)-alkyl; 4. (C2-C12)-alkenyl; 5. (C2-C8)-alkynyl; 6. -CnH2n-nn-Z wherein nn = 0 or 2; n = 0-4, and n is not or 1 if nn = 2; 7. -CnH2n-nn-Z wherein nn = 0 or 2; n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with a residue taken among a series: 1. phenyl; 3. NR(22)R(23); 5. COOR(16); R3 and R4 mean hydrogen atom; R5, R6 and R7 mean independently of one another hydrogen atom (H), (C1-C8)-alkyl; SO2-(C1-C4)-alkyl, F, Cl, Br, J, OR(10) wherein R(10) means hydrogen atom, (C1-C4)-alkyl that is substituted if necessary with methoxy- or ethoxy-group; R(9) means OR(13) wherein R(13) means hydrogen atom, H,(C1-C8)-alkyl;X means carbonyl group, -CO-CO- or sulfonyl group; Y and Z mean independently of one another: 1. phenyl, 1-naphthyl, 2-naphthyl; 2. one of residues determined in cl. 1 substituted with 1-5 similar or different residues taken among a series: phenyl, F, Cl, Br, J, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2, COR(9), or two residues form methylenedioxy-group; 3. furyl, thienyl, pyridyl, benzimidazolyl, indolyl, benzothiophenyl, dihydroquinazolinyl; 5. (C3-C10)-cycloalkyl wherein cyclopropyl, cyclopentyl, cyclohexyl and indalyl are preferable; 6. one of residues determined in cl. 5 substituted with phenyl; R(16) means: 1. hydrogen atom; 2. (C1-C4)-alkyl; 3. (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; R(19) and R(20) mean independently: hydrogen atom (H), (C1-C4)-alkyl; R(22) and R(23) mean independently of one another hydrogen atom (H) or CO-OR(24) wherein R924) means -CnH2n-phenyl wherein n = 1-4; q = 2; and their physiologically acceptable salts. Compound of the formula (I) inhibit sodium-dependent chloride-bicarbonate exchange "NCBE".

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

4 cl, 2 tbl, 568 ex

Up!