Oxadiazole derivatives possessing anti-tumor effect, medicinal agent comprising thereof and method for treatment

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new sulfonamide derivatives possessing anti-tumor activity, namely to compounds of the formula (I): wherein R6 means hydroxyl; R7 means methyl, isopropyl, isobutyl, benzyl or indole-3-ylmethyl; R8 means hydrogen atom; R9 means phenylene; R10 means thienyl, furyl or pyridyl optionally substituted with lower alkyl or halogen atom. Also, invention relates to their derivatives or pharmaceutically acceptable salts or solvates. Invention describes medicinal agents used in treatment or prophylaxis of cancer and for prophylaxis of metastasis. Also, invention describes a case for treatment of cancer in mammal.

EFFECT: improved treatment method, valuable medicinal properties of agent.

5 cl, 17 tbl, 112 ex

 

The technical field

The present invention relates to pharmaceutical compositions for the treatment or prevention of cancer comprising as active ingredient sulfonamidnuyu derived, including oxadiazolyl cycle.

The level of technology

The extracellular matrix, including collagen, fibronectin, laminin, proteoglycan and the like, performs a support function for all kinds of fabrics, but also plays an important role in migration, differentiation, adhesion, or other processes in the cell. Metalloproteinases, which are proteases containing the active site metal ion, first of all, matrix metalloproteinase (MMP), participate in the degradation of extracellular matrix. There are many MMP, MMP-1 to MMP-23.

The literature describes the MMP inhibitor with antitumor properties (see Chem. Rev., 99, 2735-2776 (1999); Current Pharmaceutical Design, 5, 787-819 (1999) and others).

It is also known that patients with cancer have seen an increased level of activity of MMP-2 and MMP-9 (see Cancer Research, 53, 878-883 (1993) and Cancer Research, 53, 5365-5369 (1993)).

It is known that MMP-9 is produced by immune cells such as macrophages and lymphocytes, and this process is regulated by cytokines (see article Journal of Immunology, 4159-4165 (1996) and Journal of Immunology, 2327-2333 (1997)). It is believed that MMP-9 is included in the process that is oment, when a cell such as a macrophage and lymphocyte destroys cellular matrix in order to approach the inflammation or tumor development. Accordingly, it is assumed that the strong inhibition of MMP-9 may reduce the immune response.

As described in WO 99/04780 sulfonamidnuyu derivative containing oxadiazolyl cycle, has inhibitory activity against MMP.

In addition, other known sulfonamidnuyu derivatives having inhibitory activity against MMP.

Description of the invention

As described above, currently under development compounds with inhibitory activity against MMP, which may find application as anticancer agents. However, there is a need to develop an inhibitor of MMP, which as a medicinal product has a higher efficiency and has less side effects.

The applicants of the present invention showed that some sulfonamidnuyu derivatives containing oxadiazolyl cycle, can be used as a highly effective and safe anticancer agent.

The present invention relates

1) to pharmaceutical compositions for the treatment and prevention of cancer comprising as active ingredient a compound of General formula is (I), the prodrug, pharmaceutically acceptable salt or MES

where

R1means NHOH, hydroxy or (ness.)alkyloxy,

R2means hydrogen, optionally substituted (ness.)alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaromatic,

R3means hydrogen, optionally substituted (ness.)alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaromatic,

R4means optionally substituted, Allen or optionally substituted, heteroaryl,

R5means optionally substituted aryl, optionally substituted heteroaryl or optionally substituted non-aromatic heterocyclic group.

More specifically, the invention relates to the object of the invention is described in the following steps 2)-6).

2) the Compound of the formula (I')

where

R6means NHOH, hydroxy or (ness.)alkyloxy,

R7means hydrogen, methyl, isopropyl, isobutyl, benzyl or indole-3-ylmethyl,

R8means hydrogen or optionally substituted (ness.)alkyl,

R9means phenylene or 2,5-theoffender,

Rsup> 10means optionally substituted thienyl, optionally substituted furyl or optionally substituted pyridyl, its prodrug or pharmaceutically acceptable salt or MES.

3) the Compound of the formula

or

where

its prodrug or pharmaceutically acceptable salt or MES.

4) a Pharmaceutical composition which contains as active ingredient a compound as described in paragraphs (2) or 3).

5) the Pharmaceutical composition according to paragraph (4) as an agent for the treatment or prevention of cancer.

6) the Pharmaceutical composition according to paragraph (4) as an agent for the prevention of metastasis.

7) the Use of the compounds according to paragraph (2) or (3) to obtain medicines for the treatment of tumor diseases.

8) a Method of treating neoplastic disease in a mammal by administration to a mammal, including human, a therapeutically effective amount of a compound according to paragraph 2 or 3).

The term (ness.)alkyl as used in the present description, separately or in combination, means a straight or branched Adewale is tnou hydrocarbon group, containing from 1 to 8 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, etc. Preferred C1-C6alkyl, more preferred C1-C3alkyl.

The term (ness.)alkenyl used in the present description, means a straight or branched monovalent hydrocarbon group containing from 2 to 8 carbon atoms and one or more double bond. Examples alkenylphenol groups include vinyl, allyl, propenyl, crotonyl, isopentenyl, various isomers butenyl, etc. are Preferable From2-C6alkenyl, preferable From2-C4alkenyl.

The term (ness.)quinil used in the present description, means a straight or branched monovalent hydrocarbon group containing from 2 to 8 carbon atoms and one or more triple bond. Quinil may contain one or more double bonds. Examples alkenylphenol group include ethinyl, 2-PROPYNYL, 3-butynyl, 4-pentenyl, 5-hexenyl, 6-heptenyl, 7-octenyl, etc. are Preferable From2-C6quinil, preferable From2-C4quinil.

The term cycloalkyl used in this description, includes cycloalkyl group containing from 3 to 8 carbon atoms. Note the market cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. are Preferable From3-C6cycloalkyl.

The term aryl, as used in this description alone or in combination with other terms includes monocyclic or condensed cyclic aromatic hydrocarbons. Examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, antrel etc.

The term aralkyl used in the present description, means the above-mentioned (ness.)alkyl, substituted by one or more of the aforementioned aryl groups in any possible position. Examples aranceles groups include benzyl, phenethyl, (2-phenethyl), phenylpropyl (for example, 3-phenylpropyl), naphthylmethyl (for example, 1-naphthylmethyl and 2-naphthylmethyl), ntrimethyl (for example, 9-antimetal), etc. are Preferred benzyl and phenylethyl.

In the case of R2or R3the preferred arylalkyl is benzyl. The term heteroaryl used in this description alone or in combination with other terms includes 5-6-membered aromatic heterocyclic group containing, in cycle one or more heteroatoms selected from the group comprising atoms of oxygen, sulfur and nitrogen, which may be condensed with cycloalkyl, aryl, non-aromatic heterocyclic group and the other heteroaryl for any possible state is. Examples of heteroaryl groups are pyrrolyl (for example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (e.g. 2-furyl, 3-furyl), thienyl (for example, 2-thienyl, 3-thienyl), imidazolyl (for example, 2-imidazolyl, 4-imidazolyl), pyrazolyl (for example, 1-pyrazolyl, 3-pyrazolyl), isothiazole (for example, 3-isothiazole), isoxazolyl (for example, 3-isoxazolyl), oxazolyl (for example, 2-oxazolyl), thiazolyl (for example, 2-thiazolyl), pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazinyl (for example, 2-pyrazinyl), pyrimidyl (for example, 2 pirimidil, 4 pirimidil), pyridazinyl (for example, 3-pyridazinyl), tetrazolyl (for example, 1H-tetrazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), indolizinyl (for example, 2-indolizinyl, 6-indolizinyl), isoindolyl (2-isoindolyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl), indazole (for example, 3-indazole), purines (for example, 8-purinol), hemolysins (for example, 2-hemolysins), ethanolic (for example, 3-ethanolic), chinolin (for example, 3-chinolin, 5-chinolin), phthalazine (for example, 1-phthalazine), naphthyridine (for example, 2-naphthyridine), hanalani (for example, 2-hanalani), hintline (for example 2-hintline), indolinyl (for example, 3-indolinyl), pteridinyl (for example, 2-pteridinyl), carbazoles (for example, 2-carbazolyl, 3-carbazolyl), phenanthridine (for example, 2-phenanthridines, 3-phenanthridine), akrid the Nile (for example, 1-acridine, 2-acridines), dibenzofurans (for example, 1-dibenzofuran, 2-dibenzofuran), benzimidazolyl (for example, 2-benzimidazolyl), benzisoxazole (for example, 3-benzisoxazole), benzoxazolyl (for example, 2-benzoxazolyl), benzoxadiazole (for example, 4-benzoxadiazole), benzisothiazolin (for example, 3-benzisothiazolin), benzothiazolyl (for example, 2-benzothiazolyl), benzofuran (for example, 3-benzofuran), sensational (for example, 2-benzothiazyl), etc.

In the case of R2the preferred heteroaryl are indolyl and imidazolyl.

In the case of R5the preferred heteroaryl are thienyl, pyridyl, dibenzofurans, isoxazolyl, tetrazolyl and pirolli. More preferred is a 2-thienyl.

The term heteroaromatic used in the present description includes the above-mentioned (ness.)alkyl, substituted by one or more of the above-mentioned heteroaryl groups in any possible position. Examples of heteroallyl are triazolylmethyl (for example, 4-triazolylmethyl), triazolylmethyl (for example, 5-thiazolyl-2-ethyl), benzothiazolyl (for example, (benzothiazol-2-yl)methyl)indolylmethane (for example, indole-3-ylmethyl), imidazolidinyl (for example, imidazol-5-ylmethyl), benzothiazolyl (for example, 2-benzothiazolylthio), indazolinone (for example, 1-indazolinone), benzotriazoles (for example, 1-benzotriazolyl), be skinrelated (for example, 2-benzamidomethyl), benzimidazolinyl (for example, 2-benzimidazolinyl), pyridylmethyl (for example, 4-pyridylmethyl), etc.

In the case of R2the preferred heteroallyl are indole-3-ylmethyl and imidazole-5-ylmethyl.

The term non-aromatic heterocyclic group, used in this description alone or in combination with other terms includes 5-7-membered nonaromatic ring containing one cycle or more heteroatoms selected from the group comprising atoms of oxygen, sulfur and nitrogen, and condensed cycle, which is associated with two or more non-aromatic rings. Examples of non-aromatic heterocyclic group are pyrrolidinyl (for example, 1-pyrrolidinyl, 2-pyrrolidinyl), pyrrolyl (for example, 3-pyrrolidyl), imidazolidinyl (for example, 2-imidazolidinyl), imidazolyl (for example, imidazolyl), pyrazolidine (for example, 1-pyrazolidone, 2-pyrazolidone), pyrazolyl (for example, pyrazolines), piperidinyl (piperidine, 2-piperidinyl), piperazinil (for example, 1-piperazinil), indolinyl (for example, 1-indolinyl), isoindoline (for example, isoindoline), morpholinyl (for example morpholino, 3-morpholinyl), 4H-1,2,4-oxazol-5-he, 1,2,3,4-tetrahydro-1,8-naphthiridine etc.

In the case of R5preferred non-aromatic geterotsiklicheskikh group are pyrazolidine, piperidine, pyrrole the sludge and morpholinyl.

The term aralen used in the present description, means a divalent group of the above-mentioned aryl. Examples of arylene are phenylene, naftilan etc. primarily 1,2-phenylene, 1,3-phenylene, 1,4-phenylene so Preferred is 1,4-phenylene.

The term heteroaryl used in the present description, means a divalent group of the above-mentioned heteroaryl. Examples of heteroaryl are theoffender, purandar, pyridinyl etc., first of all, 2,5-theoffender, 2,5-purandar etc. Preferred 2,5-theoffender.

The term (ness.)alkoxy used in the present description, means metiloksi, ethyloxy, n-propyloxy, isopropoxy, n-Butylochka, isobutoxy, sec-Butylochka, tert-Butylochka etc. Preferred metiloksi, ethyloxy, n-propyloxy, isopropoxy and n-Butylochka, more preferred metiloksi, acyloxy.

The term acyl as used in this description alone or in combination with other terms includes alkylaryl, in which the alkyl group means the above-mentioned (ness.)alkyl, and arylcarbamoyl, in which the aryl group means the above-mentioned aryl. Examples of acyl groups are acetyl, propionyl, benzoyl and the like(Ness.)alkyl and aryl can be substituted by the following substituents.

The term halogen, as used in this description, means fluorine, chlorine, b is ω and iodine. Preferred fluorine, chlorine and bromine.

The term (ness.)alkylthio used in the present description, means methylthio, ethylthio etc.

The term (ness.)allyloxycarbonyl used in the present description, means methyloxycarbonyl, ethoxycarbonyl, n-propylenecarbonate, isopropoxycarbonyl etc.

The term halogen(ness.)alkyl as used in this description alone or in combination with other terms includes the above (ness.)alkyl substituted by the above-mentioned halogen in position 1-8, preferably in position 1-5. Examples of the halogen(ness.)alkyl groups are trifluoromethyl, trichloromethyl, defloratin, triptorelin, dichlorethyl, trichlorethyl etc. Preferred trifluoromethyl.

Examples of the term halogen(ness.)alkyloxy used in the present description, are cryptometrics etc.

Examples of the term (ness.)alkylsulfonyl used in the present description, are methylsulphonyl, ethylsulfonyl etc. Preferred methylsulphonyl.

Examples of the term of acyloxy used in the present description, are the atomic charges, propionyloxy, benzoyloxy and the like

The term substituted amino, used in this description alone or in combination with other terms includes an amino group substituted by one or two of the above groups: (NISS.)alkyl, aralkyl, g is arearelated or acyl. Examples of the optionally substituted amino group are methylamino, dimethylamino, ethylmethylamino, diethylamino, benzylamino, acetylamino, benzoylamine etc. Preferred methylamino, dimethylamino, ethylmethylamino, diethylamino and acetylamino.

Examples of the term substituted aminocarbonyl used in the present description, are methylaminomethyl, dimethylaminoethyl, ethylmethylamino, diethylamino carbonyl, etc. Preferred diethylaminoethyl.

In the present description the substituents in the optionally substituted (ness.)the alkyl group are cycloalkyl, hydroxy, (ness.)alkyloxy, mercapto, (ness.)alkylthio, halogen, nitro, cyano, carboxy, (ness.)allyloxycarbonyl, halogen(ness.)alkyl, halogen(ness.)alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy, optionally substituted non-aromatic heterocyclic group, aryloxy (for example, phenyloxy), Arakelots (e.g., benzyloxy), (ness.)alkylsulfonyl, guanidino, Isograph, optionally substituted of wreid (for example, wreid, N'-methylurea) etc. These substituents can be in one or more of any possible positions.

In the present description the substituents in the optionally substituted arylene, optionally substituted heteroaryl, not necessarily replacing the hinnon the aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic group, optionally substituted aralkyl, optionally substituted heteroaromatic, optionally substituted titile, optionally substituted pyridine and optionally substituted purile are optionally substituted (ness.)alkyl, cycloalkyl, (ness.)alkenyl, (ness.)quinil, hydroxy, (ness.)alkyloxy, mercapto, (ness.)alkylthio, halogen, nitro, cyano, carboxy, (ness.)allyloxycarbonyl, halogen(ness.)alkyl, halogen(ness.)alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic group, optionally substituted aralkyl, (ness.)alkylsulfonyl, guanidinium, Isograph or optionally substituted of wreid (for example, wreid, N'-methylurea) etc. These substituents can be in one or more of any possible positions.

In the case of R4preferred unsubstituted groups are optionally substituted, Allen and optionally substituted, heteroaryl. These substituents are halogen, nitro, cyano, (ness.)alkyloxy etc.

In the case of R5preferred optional substituents in the nutrient substituted aryl, optionally substituted heteroaryl and optionally substituted non-aromatic heterocyclic group are (ness.)alkyl, hydroxy(ness.)alkyl, hydroxy, (ness.)alkyloxy, (ness.)alkylthio, halogen, nitro, carboxy, halogen(ness.)alkyl, halogen(ness.)alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl etc. More preferred substituents are halogen and (ness.)alkyl.

If R5means optionally substituted aryl, preferred are unsubstituted aryl or aryl substituted by halogen or (ness.)the alkyl.

In the case of R10preferred substituents in the optionally substituted titile, optionally substituted pyridine and optionally substituted purile are (ness.)alkyl and halogen.

In the case of R10General formula (I') are preferred 2-thienyl or 2-thienyl, substituted (ness.)by alkyl or halogen in position 5.

Preferred is a compound of General formula (I'), where R6means hydroxy, R7means methyl or isopropyl, R8means hydrogen, R9means 2,5-phenylene, R10means hydroxy, unsubstituted phenyl or phenyl substituted in position 4 by halogen or (ness.)the alkyl.

Preferred embodiments of the inventions

The compound (I) according to the invention may be a synthesis of the identified according to the methods described in WO 97/27174, or as shown in the following scheme.

Scheme 1

where R2, R4and R5have the meanings indicated above and Hal means halogen, R11is a protective group for carboxyl group.

Stage 1

This stage is a way of getting sulfonamidnuyu derivative (IV) of the starting compound (II). The method can be performed similarly as described in WO 97/27174 (method a, step 1).

Stage 2

This stage is a way of education oxadiazolines cycle by the reaction of the compound (IV) with compound (V).

The compound (IV) is dissolved in diglyme, toluene and the like, and then to the reaction mixture at a temperature of from 0°With 30°C, preferably from 0°to 20°add oxalicacid and N,N-dimethylformamide, and then the reaction mixture is stirred preferably for 60 to 120 minutes To a solution of compound (V) in diglyme and toluene while cooling with ice add a solution of acylchlorides obtained as described above, and then the reaction mixture was stirred at temperatures from 0°to 110°C for from 2 to 18 hours, preferably for from 2 to 3 p.m Compound (VI) obtained after conventional treatment of the reaction mixture.

Stage 3

This stage is a method of obtaining compound (VII) from compound (VI) removing protective the group with a carboxyl group.

Removing the protective groups are known by the method described in the monograph "Protective Groups in Organic Chemistry, Theodora W. Green (John Wiley&Sons)" etc.

The term "compounds of the present invention"used in this description, includes pharmaceutically acceptable salt and MES specified connection. Examples are salts with alkali metal (e.g. lithium, sodium and potassium), alkaline earth metal (e.g. magnesium and calcium), ammonium, organic base, an amino acid, a mineral acid (e.g. hydrochloric acid, Hydrobromic acid, phosphoric acid and sulfuric acid) or organic acid (e.g. acetic acid, citric acid, maleic acid, fumaric acid, benzosulfimide acid and para-toluensulfonate acid) and a solvate of these salts with the solvent. As MES preferred hydrate. These salt and solvate can be obtained by conventional methods. The hydrate can link steering link an arbitrary number of water molecules.

The present invention includes prodrug compounds according to the invention. A prodrug is a derivative of the compound of the present invention containing a group which can be removed by chemical or biochemical means, and such prodrug thanks solvo what she or transformation under physiological conditions in vivo turns into a pharmaceutically active compound of the present invention. The choice of technique and technology to obtain the corresponding derivative prodrugs are described in the literature, such as Design of Prodrugs, Elsevier, Amsterdam (1985). If the compounds of the present invention contain a carboxyl group, examples of prodrugs is derived in the form of ester, obtained by interaction of the original acid compound with an appropriate alcohol, or amide, obtained by the reaction of the original acid compound with the appropriate amine. First of all, as prodrugs preferred esters are methyl ester, ethyl ester, n-propyl ether, isopropyl ether, n-butyl ester, isobutyl ester, tert-butyl methyl ether, morpholinoethoxy ether, N,N-diethylaminoethyl etc. If compounds of the present invention contain hydroxyl group, examples of prodrugs are allocryptopine, obtained by the interaction with the corresponding allelochemical or anhydride. First of all, as preferred prodrugs aryloxypropanolamine are EA2H5, -OCO-tert-Bu, -OCOC15H31, -OCO(meta-COONa-Ph), -OCOCH2CH2COONa, -OCOCH(NH2)CH3and OSON2N(CH3)2etc. If the compounds of the present invention contain an amino group, examples of prodrugs of production is the second in the form of amide, obtained by the interaction with halogenerator or anhydride of the appropriate acid. First of all, as prodrugs preferred inorganic salts are-NHCO(CH2)20CH3, -NHCOCH(NH2)CH3etc.

The compound of the present invention is not limited to any particular isomer but includes all possible isomers and racemic mixture.

The compound of the present invention has a selective inhibitory activity against MMP-2 and anti-tumor activity, as shown below in the examples.

In addition, the compound of the present invention has a relatively low degree of binding to protein, is present in high concentrations in the blood and not inhibits the enzyme P-450. Therefore it has satisfactory properties for use as a medicine.

When introducing the compound of the present invention to a patient for the treatment of neoplastic diseases can be administered orally in the form of powder, granules, tablets, capsules, pills or liquid form, or parenterally in the form of injections, suppositories, percutaneous injection, blowing, etc. Effective amount of the compounds according to the invention is processed, if necessary, by mixing with an appropriate pharmaceutical additive such as excipient linking agent, wetting agent, dezintegriruetsja agents, sizing, etc. In the manufacture of drugs for injection, the compound according to the invention and the corresponding carrier is sterilized.

The appropriate dosage varies according to the condition of the patient, method of administration, patient's age and body mass. When administered orally to adults, the dosage is usually from 0.01 to 100 mg/kg/day, preferably from 0.1 to 20 mg/kg/day.

The present invention is illustrated by the following examples without limiting its scope.

The examples use the following abbreviations.

Me - methyl

Et is ethyl.

n-Pr n-propyl

i-Pr is isopropyl

n-Bu is n-butyl

i-Bu is isobutyl

t-Bu is tert-butyl

Ph - phenyl

Bn - benzyl

DMSO - dimethyl sulfoxide

EXAMPLES

Example 1

Obtaining the compounds a-1

Scheme 2

Stage 1

To a solution of methyl ester hydrochloride D-valine (1) (8,2 g and 40.8 mmole) in water (100 ml) under ice cooling was added sodium carbonate (8.65 g) and acetone (80 ml). To the mixture was added water (50 ml), 4-chlorosulfonylbenzoic acid (2) (6 g, of 27.2 mmole) and the reaction mixture was stirred under ice cooling for 2 hours Then the reaction mixture was poured into ice 2 M hydrochloric acid and was extracted with ethyl acetate. About the organic layer was washed with saline, was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After recrystallization of the residue from ethyl acetate or acetone/hexane was obtained compound (3) (6.2 g, 79.3 percent), tpl.197-199°C.

IR (KBr, υmaxcm-1): 3500-2500, 3296, 3259, 1739, 1718, 1689, 1344, 1171.

1H NMR (DMSO-d6, part./million): of 1.88 (d, J 7.2 Hz, 3H), 3,42 (s, 3H), of 3.94 (m, 1H), 7,88 (d, J 8,4 Hz, 2H), 8,11 (d, J 8,4 Hz, 2H), charged 8.52 (d, J 8.7 Hz, 1H), 13,35 (.s, 1H).

[α]D+23,1±1,2 (0,507, DMSO, 23°).

Elemental analysis for C11H13NO6S:

Rasch.: With 45.99 per, N 4,56, N 4,88, S 11,16,

calc.: WITH 45,57, N 4,40, N 4,87, S 11,10.

Stage 2

To a solution of compound (3) (23,61 g, 82.2 mmole) in diglyme (240 ml) was added oxalicacid (at 8.60 ml, 98,6 mmole), N,N-dimethylformamide (0.2 ml)and the reaction mixture was stirred at room temperature for 80 minutes To a solution of compound (4) (12,34 g, 82.2 mmole), pyridine (20 ml, 247 mmol) and diglyme (130 ml) under ice cooling was added a solution of acylchlorides obtained as described above, and the reaction mixture was stirred at room temperature for 1.5 h at 110°C for 1 h, the Reaction mixture was cooled to 40°C for 1 h, the supernatant was poured into ice water (400 ml) and the mixture was stirred for 1 h the resulting crystals were separated by filtration, washed with water, and then dissolved in ethyl acetate. The organic layer consequently is washed with 2 M hydrochloric acid (100 ml), saturated aqueous sodium hydrogen carbonate (100 ml) and brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. After recrystallization of the residue from ethyl acetate/hexane was obtained compound (5) (22,64 g, 68,6%), tpl.148-150°C.

IR (KBr, νmaxcm-1): 3440. 3284, 1743, 1346, 1169, 1133.

1H NMR(CDCl3, part./million): USD 1.43 (d, J 7.2 Hz, 3H), of 2.44 (s, 3H), of 3.57 (s, 3H), 4,08 (m, 1H), 5,35 (d, J 8,4 Hz, 1H), 7,33 (d, J 8.1 Hz, 2H), 8,03 (d, J 9.0 Hz, 2H), of 8.06 (d, J 8.1 Hz, 2H), at 8.36 (d, J 9.0 Hz, 2H).

[α]D+17,8±1,2 (with worn : 0.505, DMSO, 24°).

Elemental analysis for C19H19N3O5S:

Rasch.: With 56,84, N 4,77, N 10,47, S 7,99,

calc.: WITH 57,21, N 4,77, N 10,61, S 7,89.

Stage 3

To a solution of compound (5) (22,64 g, 56,50 mmole) in dimethyl sulfoxide (230 ml) at room temperature was added 1 M sodium hydroxide solution (141 ml) and the reaction mixture was stirred for 18 h the resulting solution of sodium salt was filtered, washed with ethyl acetate (100 ml)was poured into ice 2 M hydrochloric acid (100 ml) and was extracted twice with ethyl acetate/tetrahydrofuran (10:1, 300 ml, 200 ml). The organic layer was washed brine (2×200 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure.

After recrystallization of the residue from ethanol/water was obtained compound (6) (17,70 g, 81,0%), tpl.maxcm-1): 3240, 1726, 1346, 1151.

1H NMR (DMSO-d6, part./million): of 1.20 (d, J 7.5 Hz, 3H), 2,41 (s, 3H), 3.87 (m, 1H), 7,43 (d, J 8.1 Hz, 2H), 8,01 (d, J 8.1 Hz, 2H), 8,04 (d, J 8.1 Hz, 2H), at 8.36 (d, J 8.1 Hz, 2H), 8,48 (m, 1H), 12,80 (.s, 1H).

[α]365-12,2±1,0 (0,502, DMSO, 24°).

Elemental analysis for C18H17N3O5S:

Rasch.: With 55,80, N 4,42, N 10,85, S 8,28,

calc.: With 55,52, N 4,46, N 10.81, S 8,23.

Example 2

Getting connections a-2

Scheme 3

Stage 1

To a solution of methyl ester hydrochloride D-valine (6) (18,12 g, 84 mmole) in water (100 ml) under ice cooling was added a 2 M aqueous solution of sodium carbonate (61,25 ml), 4-chlorosulfonylbenzoic acid (2) (16,09 g, 70 mmol) and the reaction mixture was stirred at room temperature for 3 h Then the reaction mixture was poured into ice 2 M hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. After recrystallization of the residue from acetone/hexane was obtained compound (7) (21,56 g, 84,8%), tpl.188-189°C.

IR (KBr, νmaxcm-1): 3280, 2956, 1737, 1691, 1428, 1346, 1284, 1166, 723.

1H NMR (DMSO-d6, part./million): 2,77 (dd, J of 9.3 and 13.5 Hz, 1H), equal to 2.94 (dd, J 5,7, and 13.5 Hz, 1H), 3,37 (s, 3H), 4,01 (dt, J of 6.0, 9.0 Hz, 1H), 7,08-of 7.23 (m, 5H), 7,66 (d, J 8,4 Hz, 2H), of 7.97 (d, J 8.4 and the C, 2H), 8,69 (d, J 9.0 Hz, 1H), 13,38 (.s, 1H).

[α]D+3,2±0,9 (with worn : 0.505, DMSO, 24°).

Elemental analysis for C17H17NO6S:

Rasch.: With 56,19, N 4,72, N Of 3.85, S 8,82,

calc.: WITH 56,06, N OF 4.57, N 3,93, S 8,75.

Stage 2

To a solution of compound (7) (20,0 g, 55 mmole) in diglyme (200 ml) was added oxalicacid (5,67 ml, 66 mmol), N,N-dimethylformamide (0.2 ml) and the reaction mixture was stirred at room temperature for 1 h To a solution of benzamidoxime (7,49 g, 55 mmol) and diglyme (75 ml), placed in another reaction vessel, while cooling with ice was added pyridine (14.1 ml, 165 mmol), and then also while cooling with ice a solution of acylchlorides, obtained as described above, and the reaction mixture was stirred at the same temperature for 1 h and at 110°C for 2 h, the Reaction mixture was cooled to room temperature, the supernatant was poured into ice water (400 ml) and the mixture was stirred for 20 minutes the precipitate was separated by filtration, washed with diethyl ether and recrystallization from acetone/hexane was obtained compound (8) (16.5 g, 64.9%, respectively), tpl.160-161°C.

IR (KBr, νmaxcm-1): 3338, 1745, 1342, 1169.

1H NMR (CDCl3, part./million): 2,99-3,14 (m, 2H), of 3.56 (s, 3H), 4,29 (m, 1H), 5,19 (d, J 9.0 Hz, 1H), 7,05-to 7.09 (m, 2H), 7.23 percent-7,26 (m, 3H), 7,51-7,56 (m, 3H), 7,89 (d, J 8.7 Hz, 2H), 8,16-8,19 (m, 2H), of 8.27 (d, J 8.7 Hz, 2H).

[α]D-6,8±0,9° (0,509, DMSO, 24°).

p> Elemental analysis for C24H21N3O5S:

Rasch.: With 62,19, N Of 4.57, N 9,07, S 6,92,

calc.: WITH 62,02, N TO 4.52, N 8,95, S OF 6.96.

Stage 3

To a solution of compound (7) (to 4.41 g of 9.51 mmole) in dimethyl sulfoxide (85 ml) at room temperature was added 1 M aqueous sodium hydroxide solution (28,5 ml) and the reaction mixture was stirred for 24 h Obtained sodium salt was filtered, poured into ice 2 M hydrochloric acid (100 ml) and was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saline, dried over sodium sulfate and concentrated under reduced pressure. After recrystallization of the residue from ethanol/water was obtained compound (8) (3.80 g, 88,8%), tpl.221-222°C.

IR (KBr, νmaxcm-1): 3286, 1720, 1350, 1167.

1H NMR(DMSO-d6, part./million): to 2.74 (dd, J 9,6, to 13.6 Hz, 1H), 3,00 (dd, J 5.0 and a 13.8 Hz, 1H), 4.00 points (m, 1H), 7,02-7,22 (m, 5H), 7,56-7,72 (m, 2H), 7,79 (d, J 7.8 Hz, 2H), 8,13 (m, 2H), 8,21 (d, J 8,4 Hz, 2H), 8,63 (d, J 8,4 Hz, 1H), 12,86 (.s, 1H).

[α]D+1,6±0,9° (0,502, DMSO, 24,5°).

Elemental analysis for C23H19N3O5S:

Rasch.: With 61,46, N 4.26 Deaths, N 9,35, S 7,13,

calc.: WITH 61,40, N 4,15, N 9,41, S 7,16.

Example 93

The connection is A-93

Scheme 4

Stage 1

To a solution of sodium carbonate (14.4 g, 135,9 mmole) in acetone (100 ml) and water (100 ml) at room temperature we use the hydrochloride and methyl ester of D-valine (9) (9,1 g, 54,3 mmole), 4-chlorosulfonylbenzoic acid (2) (10.0 g, 45,3 mmole) and the reaction mixture was stirred at room temperature for 1.5 hours Then the reaction mixture was poured into ice 2 M hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. After recrystallization of the residue from ethyl acetate/hexane (1:3) was obtained compound (10) (9,84 g, 68.8 per cent), tpl.213-215°C.

IR (KBr, νmaxcm-1): 3268, 2965, 1737, 1691, 1430, 1344, 1284, 1168.

1H NMR (DMSO-d6, part./million): to 0.80 (t, J 6.6 Hz, 6N), of 1.93 (m, 1H), 3,34 (s, 3H), of 3.60 (dd, J 7,2, 9,3 Hz, 1H), 7.24 to 7,89 (m, 2H), 8,06-8,11 (m, 2H), of 8.47 (d, J 9.3 Hz, 1H).

[α]D+7,6±1,0 (0,502, DMSO, 25°).

Elemental analysis for C13H17NO6S·0,1 H2O:

Rasch.: With 49,23, N 5,47, N 4,42, S 10,11,

calc.: WITH 49,17, N ARE 5.36, N 4,39, S 10,30.

Stage 2

To a solution of 5-methylthiophene-2-carboxylic acid (11) (20,3 g, 143 mmole) in tetrahydrofuran (200 ml) under ice cooling was added N,N-dimethylformamide (0.1 ml), oxacillin (18,4 ml, 211 mmol) and the reaction mixture was stirred at room temperature for 4 h Then the reaction mixture was poured into ice 28%aqueous ammonium hydroxide solution and was extracted with ethyl acetate. The organic layer was washed with saline, dried nadaswaram sodium sulfate and concentrated under reduced pressure. After recrystallization of the residue from ethyl acetate/hexane (1:3) was obtained compound (12) (19,61 g, 97,3%), tpl.162-163°C.

IR (KBr, νmaxcm-1): 3374, 3170, 1658, 1608, 1469, 1396, 1376.

1H NMR (DMSO-d6, part./million): of 2.45 (s, 3H), for 6.81 (dd, J 1,2, 3,9 Hz, 1H), 7,27 (.s, 1H), 7,53 (d, J 3.9 Hz, 1H), 7,84 (.s, 1H).

Elemental analysis for C6H7NOS:

Rasch.: With 51,04, N. 5,00, N 9,92, S 22,71,

calc.: WITH 50,93, N 4,86, 9,81 N, S ONE-22.67.

Stage 3

To a suspension of compound (12) (19,0 g, 135 mmol) in toluene (76 ml) was added thionyl chloride (49,0 ml, 675 mmol) and the reaction mixture was stirred at 100°C for 7 h and Then the reaction mixture was poured into ice saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layer was washed with saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oily compound (13) (22 g) was used in the next stage without purification.

1H-NMR (CDCl3, part./million): 2.54 (d, J 0.6 Hz, 3H), 6,78 (m, 1H), 7,44 (d, J 3.3 Hz, 1H).

Stage 4

To a suspension of compound (13) (22 g) and chloride of hydroxylamine (11.3 g, 163 mmol) in ethanol (160 ml) at room temperature was added triethylamine (and 22.6 ml, 163 mmol) and the reaction mixture was stirred at 100°C for 2 hours, the Ethanol was removed under reduced pressure, to the residue was added water and the mixture of extras who were garofali with ethyl acetate. The organic layer was washed with saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. After recrystallization of the residue from ethyl acetate/hexane (1:3) was obtained compound (14) (11,32 g, 53.6% in the calculation of the two-stage).

IR (KBr, νmaxcm-1): 3390, 3072, 1643, 1585, 1492, 1390, 1371, 931, 808.

1H NMR (DMSO-d6, part./million): 2,39 (s, 3H), of 5.82 (s, 2H), 6,45 (dt, J 3,3, 0.9 Hz, 1H), 7,24 (d, J 3.3 Hz, 1H), 9,52 (s, 1H).

Elemental analysis for C6H8N2OS:

Rasch.: With 46,13, N 5,16, N 17,93, S 20,53,

calc.: WITH 46,09, N OF 5.05, N 17,87, S 20,69.

Stage 5

To a suspension of compound (10) (9.80 g, 31,1 mmole) in diglyme (100 ml) at room temperature was added oxalicacid (3,30 ml, 98,6 mmole), N,N-dimethylformamide (1.0 ml) and the reaction mixture was stirred for 2 hours To a solution of compound (14) (4,85 g, 31,1 mmole), pyridine (7,50 ml of 92.7 mmole) and diglyme (50 ml) under ice cooling was added a solution of acylchlorides, obtained as described above, and the reaction mixture was stirred at room temperature for 2 h at 110°C for 4 h the Reaction mixture was stirred at room temperature overnight. The supernatant was poured into ice water (400 ml), the resulting crystalline precipitate was separated by filtration and dissolved in ethyl acetate. The mixture is then washed with 2 M hydrochloric acid, saturated aqueous bicarbonate is the atrium and a salt solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After recrystallization of the residue from ethyl acetate/hexane (1:3) was obtained compound (15) (9,07 g, 67.0 per cent), tpl.155-157°C.

IR (KBr, νmaxcm-1): 3459, 3280, 1737, 1511, 1365, 1346, 1205, 1170, 1139, 1120, 755.

1H NMR (CDCl3-d6, part./million): 0,88 (d, J 7.2 Hz, 3H), and 0.98 (d, J 6.6 Hz, 3H), of 2.08 (m, 1H), 2,58 (d, J 0.9 Hz, 3H), of 3.48 (s, 3H), 3,83 (dd, J of 4.8, 9.9 Hz, 1H), 5,22 (d, J=9.9 Hz, 1H), 6,85 (dd, J of 0.9, 3.6 Hz, 1H), 7,69 (d, J 3.6 Hz, 1H), 8,01 (d, J 8.7 Hz, 2H), 8,32 (d, J 8.7 Hz, 2H).

[α]D+2,8±0,9 (0,506, DMSO, 20°).

Elemental analysis for C19H21N3O5S:

Rasch.: With 52,40, N. A 4.86, N 9,65, S 14,73,

calc.: WITH 52,33, N 4,73, N 9,62, S OF 14.90.

Stage 6

To a solution of compound (15) (9.0 g, 20,7 mmole) in dimethyl sulfoxide (186 ml) at room temperature was added 1 M aqueous sodium hydroxide solution (62,0 ml) and the reaction mixture was stirred at 50°C for 24 h Then the reaction mixture was poured into ice 2 M hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. After recrystallization of the residue from acetone/water was obtained compound (A-93) (8,4 g, 96,3%), tpl.208-210°C.

IR (KBr, νmaxcm-1): 3284, 2971, 1712, 1556, 1508, 1403, 1365, 1349, 1253, 1180, 1164, 1145, 1093, 755.

1H AMTSO-d 6, part./million): 0,82 (d, J 6.9 Hz, 3H), of 0.85 (d, J 6.6 Hz, 3H), of 1.98 (m, 1H), has 2.56 (s, 3H), 3,61 (dd, J of 6.6, and 7.8 Hz, 1H), 7,02 (m, 1H), 7,72 (dd, J 1.5 and 3.6 Hz, 1H), 8,00-of 8.06 (m, 2H), 8,29-of 8.25 (m, 2H), of 8.37 (d, J 7.8 Hz, 1H), 12,65 (.s, 1H).

[α]D-13,4±1,1 (0,509, DMSO, 25°).

Elemental analysis for C18H19N3O5S2:

Rasch.: With 51,29, N Of 4.54, N 9.97, S 15,22,

calc.: WITH 51,05, N 4,42, N 9,92, S 15,12.

Compounds (a-3)-(a-92) and (94)-(a-108)described in tables 1-15, synthesized similarly as described above.

Biological tests

Example 1

Isolation and purification of matrix metalloproteinases (MMP)

MMP-2 was received at the company Calbiochem-Novabiochem International, Inc., MMP-9 was received at the company Calbijchem-Novabiochem International, Inc.

The DNA fragment corresponding to the catalytic domain of MMP-8 (99Phe˜262Gly), amplified by PCR using specific Primero and cDNA from human bone marrow, which are commercial products. The DNA fragment was cloned into the E. coli expression vector rthsa containing the sequence His-tag and the site of cleavage by enterokinase. The expression of the catalytic domain of MMP-8 was induced by adding IPTG (isopropyl-β-D-thiogalactopyranoside), it was obtained a residue of cells containing the catalytic domain of MMP-8. (Used partially modified method described in the article Thau f, M. Walid Qoronfleh, Robert C. Wahl, Trica A. Pulvino, Karen J. Vavra, Joe Falvo, Tracey M. Banks, Patricia G. Brake and Richard B. Ciccarelli, Gene expression, purification and characterization of recombinant human neutrophil collagenase, Gene, 146, 297-301 (1994)). The secretion of MMP-8 from the cell sediment was performed by standard methods. After dissolution of the cell sediment in 6 M urea solution was applied onto a sorbent for metalochelates chromatography. Further removal of urea and renaturation of MMP-8 was used dialysis, received active MMP-8.

Example 2

Determination of inhibitory activity against MMP

The enzymatic activity of MMP was determined using the method described in the article by C. Graham Knight, Frances Willenbrock and Gillian Murphy, A novel coumarin-labelled peptide for sensitive continuous assays of the matrix metalloproteinases, FEBS Lett., 296, 263-266 (1992). The substrate (Moss-Pro-Leu-Gly-Leu-A2Pr(DNP)-Ala-Arg-NH2) were obtained on the firm Peptide Institute Inc., Osaka, Japan.

Determination of inhibitory activity (IC50) conducted the following four methods:

a) Interaction with the substrate, the enzyme (MMP) and inhibitor.

b) Interaction with substrate and inhibitor in the absence of the enzyme.

C) Interaction with substratum and the enzyme in the absence of inhibitor.

d) Interact with the substrate.

The value of the IC50was calculated by the following formula using values of fluorescence obtained by using the above four methods (a-d).

% inhibition = {1-(a-b)/(b-g)}×100

The value of the IC50means the concentration required to inhibit enzyme activity by 50%.

The results are presented in table 16.

Table 16
Connection # MMP-2 (nm)MMP-8 (nm)MMP-9 (nm)
A-130>1000470
A-253>1000>1000
A-315775384
A-426>1000190
A-530610>1000
A-650>1000>1000
A-78>100078
A-851>1000479
A-918>1000566
A-1065>1000>1000
A-9368847

Example 3

Method of assessing antitumor activity using artificial metastasis in lung carcinoma lung of mice Lewis

Cell lung carcinoma mice Lewis (4×10 cells) were inoculated into the tail vein of mice BDF1. The analyzed compounds suspended in medium (0.5%solution of methylcellulose) and five was administered to mice by oral way (for 4 h before inoculation of the tumor and after 1, 24, 48 and 72 h after inoculation of tumor). Doses of the compounds was 20 and 200 mg/kg or 2 and 20 mg/kg After 14 days after inoculation of tumor in the lungs of experimental mice were counting the number of colonies of tumor cells and assessed the antitumor activity of the analyzed compounds. The compound (B-1) was used as a sample for comparison. The results are given in table 17.

Table 17
Example No.Connection # Quantity (mg/kg)The number of colonies(environments. Val. ±+)Inhibition (%)
3-1Control-42,8±a 12.70
In-12026,5±19,538
In-120023,0±7,6*46
A-12020,2±13,3*53
A-120013,3±11,8**69
A-42019,2±9,4**55
A-420023,3±12,8*46
A-72018,8±6,9**56
A-720021,7±9,6**49
A-82018,8±11,4**56
A-820015,7±5,5**63
A-102024,5±7,8*43
A-10 20025,2±17,041
3-2Control-55,2±13,60
In-12034,8±14,5*37
In-120038,3±20,731
A-22034,8±19,537
A-220030,2±13,9*45
A-52041,8±22,524
A-520034,8±12,1*37
A-62040,8±13,526
A-620024,0±9,7**57
A-92038,7±5,8*30
A-920027,0±9,7**51
3-3Control-61,8±7,90
In-1253,5±18,5 14
In-12037,5±13,0**39
A-93236,3±9,2**41
A-932030,8±10,8**50
+WITH standard deviation

Table 16 shows that the compounds selectively inhibit MMP-2.

Table 17 shows that the compounds possess significant inhibitory effect on the metastasis and growth of cancer cells.

The examples of the preparation of medicinal compositions

Part 1

Pellets were obtained using the following ingredients.

Ingredients:The compound of formula (I)10 mg
Lactose700 mg
Corn starch274 mg
HPC-L16 mg
1000 mg

The compound of formula (I) and lactose were sifted through a sieve of 60 mesh. Corn starch were sieved through a sieve of 120 mesh. Then the components were mixed in the mixer with double the sheath. To the mixture was added an aqueous solution of HPC-L (hydroxypropylcellulose with a low viscosity) and the resulting mixture was mixed until a homogeneous mass was granulated (using extrusion through holes ranging in size from 0.5 to 1 mm) and dried. Thus obtained granules were screened through a vibrating sieve (12/60 mesh) to obtain granules.

Part 2

Powders for filling capsules were obtained using the following ingredients.

Ingredients:The compound of formula (I)10 mg
Lactose79 mg
Corn starch10 mg
Magnesium stearate1 mg
100 mg

The compound of formula (I) and lactose were sifted through a sieve of 60 mesh. Corn starch were sieved through a sieve of 120 mesh. These components and magnesium stearate were mixed in a mixer with a double shell. After a 10-fold trituration with a mixture (100 mg) was filled in hard gelatin capsule No. 5.

Part 3

Granules for filling capsules were obtained using the following ingredients.

Ingredients:The connection f is rmula (I) 15 mg
Lactose90 mg
Corn starch42 mg
HPC-L3 mg
150 mg

The compound of formula (I) and lactose were sifted through a sieve of 60 mesh. Corn starch were sieved through a sieve of 120 mesh. After mixing of the components was added an aqueous solution of HPC-L and the resulting mixture was mixed until a homogeneous mass was granulated and dried. Then the dried granules were treated (watered) and a weight of 150 mg was filled in hard gelatin capsule No. 4.

Part 4

Tablets were obtained using the following ingredients.

Ingredients:The compound of formula (I)10 mg
Lactose700 mg
Microcrystalline cellulose30 mg
CMC-Na15 mg
Magnesium stearate5 mg
150 mg

The compound of formula (I), lactose, microcrystalline cellulose and CMC-Na (sodium salt of carboxymetilcellulose is) was sifted through a sieve of 60 mesh, and then mixed. The resulting mixture was mixed with magnesium stearate to obtain a powder mixture, which is extruded, receiving tablets weighing 150 mg

Industrial applicability

Sulfonamidnuyu derivatives containing oxadiazole ring of the present invention have inhibitory activity against metalloprotease, first of all, MMP-2, and can be used as agents for treatment or prevention of malignant neoplastic diseases.

1. The compound of formula (I/)

(I/)

where

R6means hydroxyl,

R7means methyl, isopropyl, isobutyl, benzyl or indole-3-ylmethyl,

R8means hydrogen,

R9means phenylene,

R10means thienyl, furyl or pyridyl, optionally substituted lower alkyl or halogen;

its derivatives, representing an ester, acrosiphonia or derivatives or pharmaceutically acceptable salt or MES.

2. Connection on p. 1 of the formula

its derivatives, representing an ester, acrosiphonia or derivatives or pharmaceutically acceptable salt or MES.

3. Drug for treatment is or prevention of cancer, containing compound under item 1 or 2.

4. Medicinal product for the prevention of metastasis containing compound under item 1 or 2.

5. A method of treating cancer in a mammal by administration to a mammal, including human, a therapeutically effective amount of the compounds under item 1 or 2.



 

Same patents:

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes using 2-morpholyl-6-piperidyl-4-[(4'-(ethoxycarbonyl-5'-1',2',3'-triazol)-1'-yl]-1,3,5-triazine of the formula: as an antidote against phytotoxic effect of herbicide 2,4-dichlorophenoxyacetic acid on sunflower germinated seeds. The proposed substance allows significant increasing roots and hypocotyls length of seedlings and to expand assortment of the known antidotes.

EFFECT: improved and valuable properties of antidote.

2 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to new derivatives of piperidine of the general formula (II): or their pharmaceutically acceptable salts wherein Xa means -C(R13)2-, -C(R13)(R19)-, -C(O)-, and others; Ra means R6a-phenyl or phenyl substituted with methylsulfonyl; R1 means hydrogen atom or (C1-C6)-alkyl; R2 means R7-, R8-, R9-phenyl wherein R7-, R8 and R9 mean substituted 6-membered heteroaryl and others; R3 means R10-phenyl, pyridyl and others; R4 means hydrogen atom, (C1-C6)-alkyl, fluoro-(C1-C6)-alkyl; R6a means from 1 to 3 substitutes taken among the group involving hydrogen, halogen atom, -CF3 and CF3O-; R7 and R8 mean (C1-C6)-alkyl and others; R9 means R7, hydrogen atom, phenyl and others; R10 means (C1-C6)-alkyl, -NH2 or R12-phenyl wherein R12 means hydrogen atom, (C1-C6)-alkyl and others; R13, R14, R15 and R16 mean hydrogen atom or (C1-C6)-alkyl; R17 and R18 in common with carbon atom to which they are bound form spirane ring comprising from 3 to 6 carbon atoms; R19 means R6-phenyl wherein R6 means R6a or methylsulfonyl; R20, R21 and R22 mean hydrogen atom or (C1-C6)-alkyl; R23 means (C1-C6)-alkyl under condition that if Ra means phenyl substituted with methylsulfonyl then Xa can mean the group only. Compounds of the formula (II) possess properties of CCR5-antagonist and can be used in medicine in treatment of HIV-infection.

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

15 cl, 1 dwg, 12 tbl, 15 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention describes a new compound 4,6-bis-(morpholyl)-2-[(2'-ethoxyacetyltetrazolyl)-5'-yl]-1,3,5-triazine of the formula: that represents an antidote against phytotoxic effect of herbicide 2,4-dichlorophenoxyacetic acid on germinating sunflower seeds and seedlings.

EFFECT: valuable properties of compound.

2 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

FIELD: organic chemistry, heterocyclic compounds, medicine.

SUBSTANCE: invention relates to derivatives of piperazine and piperidine of the formula (I): wherein ---Z represents =C or -N; Q means benzyl or 2-, 3- or 4-pyridylmethyl that can be substituted with one or more substitutes taken among group comprising halogen atom, cyano-group, (C1-C3)-alkoxy-group, CF3, OCF3, SCF3, (C1-C4)-alkyl, (C1-C3)-alkylsulfonyl and their salts, and to a method for their preparing also. It has been found that these compounds elicit valuable pharmacological properties owing to combination of (partial) agonism with respect to members of dopamine receptors subtype and affinity with respect to corresponding serotonin and/or noradrenergic receptors and can be useful in preparing compositions used in treatment of fear and/or depression or Parkinson's disease.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 3 ex

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of azole of the formula:

wherein R1 represents (1) halogen atom; (2) nitrogen-containing 5- or 6-membered heterocyclic group comprising from 1 to 4 nitrogen atoms as atoms of ring system in addition to carbon atoms, and group with condensed rings comprising nitrogen-containing 5- or 6-membered heterocyclic group comprising 1-2 nitrogen atoms as atoms of ring system in addition to carbon atoms, and benzene ring wherein nitrogen-containing 5- or 6-membered heterocyclic group and group with condensed rings can comprise optionally from 1 to 3 substituted taken among group consisting of: (i) aliphatic hydrocarbon group comprising from 1 to 15 carbon atoms; (ii) (C6-C14)-aryl group, and (iii) carboxy-group that can be in form of group of (C1-C6)-alkyl ester wherein above indicated substitutes (i)-(iii) can have from 1 to 3 substituted additionally taken among group consisting of: (a) carboxyl group and (b) hydroxy-group; (3) (C1-C10)-alkylsulfanyl group that can be substituted with hydroxy-group; (4) heteroarylsulfanyl group taken among pyridylsulfanyl, imidazolylsulfanyl and pyrimidinylsulfanyl, or (5) amino-group that can be mono- or di-substituted optionally with substitutes(substitutes) among group consisting of: (i) (C1-C10)-alkyl group that can be substituted with hydroxy-group, and (ii) (C7-C10)-aralkyl group; Ab represents aryloxy-group that is substituted with alkyl group and can be substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl group, hydroxy-group or (C1-C6)-alkylcarbonyloxy-group additionally; B represents (C6-C14)-aryl group or thienyl group each of that can has optionally from 1 to 4 substitutes taken among halogen atom, (C1-C6)-alkoxy-group and (C1-C6)-alkyl group that can has optionally from 1 to 3 halogen atoms; Y represents saturated aliphatic bivalent group with direct or branched chain and having from 1 to 7 carbon atoms, or to its salt. Also, invention relates to a pharmaceutical composition that elicits activity for promoting production/secretion of neurotrophine, and to methods for prophylaxis and treatment based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used for prophylaxis and treatment of neuropathy.

EFFECT: improved and valuable medicinal properties of agent, improved methods for treatment.

19 cl, 1 dwg, 5 tbl, 122 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

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

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):

wherein Y means lower alkylene; R1 means phenyl with 1 or 2 substitutes taken among group consisting of trihalogen-(lower)-alkyl, halogen atom, lower alkylamino-, di-(lower)-alkylamino- and nitro-group; R2 means phenyl or indolyl and each comprises 1 or 2 substitutes taken among group consisting of lower alkyl, trihalogen-(lower)-alkyl, lower alkylene dioxy-, hydroxy-group, hydroxy-(lower)-alkyl, lower alkoxy- lower alkylamino- and di-(lower)-alkylamino-group; R3 means hydrogen atom; R4 means morpholinyl-(lower)-alkyl comprising 1 or 2 substitutes taken among group consisting of ethyl, hydroxy-(lower)-alkyl, halogen-(lower)-alkyl and lower alkoxy-(lower)-alkyl, or morpholinyl-(lower)-alkynyl that can comprise 1 or 2 substitutes taken among group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo-(lower)-alkyl, lower alkoxy-(lower)-alkyl, hydroxy-(lower)-alkyl, carboxy-(lower)-alkyl, di-(lower)-alkyl-carbamoyl, lower alkoxycarbonyl and halogen-(lower)-alkyl. Also, invention relates to a method for preparing, pharmaceutical composition based on these compounds and a method for treatment of tachykinine-mediated diseases, such as respiratory diseases, ophthalmic, cutaneous, inflammatory diseases, and as analgetic agents. Describes compounds are antagonists of tachykinine.

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

8 cl, 94 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active ortho-substituted nitrogen-containing bis-aryl compounds. Invention describes compounds of the formula (I): wherein A1, A2, A3, A4, A5, A6, A7 and A8 mean independently of one another nitrogen atom or -CH and wherein at least one or two (not above) these groups mean nitrogen atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x has a value 0, 1, 2, 3 or 4 and R(14) means alkyl c 1, 3, 4, 5 or 6 carbon atoms, phenyl or isoxazolyl wherein phenyl and isoxazolyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J, CF3, OCF3, alkyl with 1, 2, 3 or 4 carbon atoms and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(2) means hydrogen atom; R(3) means CyH2y-R(16) wherein y has a value 0, 1, 2, 3 or 4but y can't mean 0 if R(16) means -OR(17), and R(16) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3 carbon atoms, -OR(17), phenyl or pyridyl wherein phenyl and pyridyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(17) means hydrogen atom; or R(3) means -CHR(18)R(19) wherein R(18) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms and R(19) means -CONH2; R(4) means hydrogen atom; R(30) and R(31) mean hydrogen atom, and their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition showing effect that inhibits K+-channel and comprising the effective amount of at least compound of the formula (I) and using compounds of the formula (I). Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 8 tbl, 35 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-aminomethylquinolone-2 of the general formula (1)

(2)

or (3) wherein R1 means hydrogen atom (H) or Alk; R2 is taken among Alk; -OAlk, -SCH3, -Hal, -CF3, 3,4-OCH2CH2O-, 3,4-OCH2O-, 4-OCF3, 2-Ph, -OPh, -NHCOR, 2-OCH3, 5-Ph, 4-Obzk, 3-NO2, 2-CH3, 5-iPr, di-OAlk, di-Hal; or R2 represents halogen atom and alkyl group, or halogen atom and alkoxy-group taken simultaneously and independently of one another; or R2 represents the group -CONR4R5 wherein each R4 and R5 means independently of one another the group Alk, or they form the group -(CH2)n- wherein n = 2-6. R means -CH3; R3 means hydrogen atom (H); X is taken among hydrogen atom (H), 6-(C1-C3)-Alk, 6-iPr, 6-iBu; 7-(C1-C2)-Alk, 8-(C1-C2)-Alk, 6-(C1-C2)-OAlk, 6-OCF3, 7-(C1-C2)-Alk, 7-SCH3, 6,7-OCH2O-, 6,7-OCH2CH2O-, 5,6,7-OCH3, 6-F; X and Y are similar or different and taken among 7,8-CH3, 6,8-CH3, 5,8-CH3, 5,7-CH3, 6,7-CH3, 6,7-OCH3, 6-CH3, 7-Cl. Also, invention relates to a method for preparing indicated compounds and to pharmaceutical composition inhibiting activity of NO-synthetase based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof for aims preparing medicinal agents for treatment diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

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

19 cl, 1 tbl, 95 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula (1):

wherein R1 means (C1-C6)-alkyl that can be substituted once or multiply with phenyl; R2 and R3 means independently of one another hydrogen atom, (C6-C10)-aryl, (C3-C8)-cycloalkyl, (C6-C10)-aryloxymethyl, O-benzyl can be substituted once or multiply with halogen atom, -CF3,, O-(C6-C10)-aryl or O-(C3-C8)-cycloalkyl, O-(C1-C6)-alkyl, that can be substituted once or multiply with fluorine atom or amino-group wherein amino-group, in turn, can be substituted once or multiply with (C1-C4)-alkyl; SO2-NH-(C1-C6)-alkyl substituted possibly with group N-[(C1-C6)-alkyl]2; SO2-NH-(2,2,6,6-tetramethylpiperidin-4-yl); SO2-NH-(C3-C8)-cycloalkyl substituted possible once or multiply with (C1-C4)-alkyl; SO2-N-[(C1-C6)-alkyl]2 or COX wherein X means N-[(C1-C6)-alkyl]2; and N-[(C1-C6)-alkyl-alkyl]2 can mean also pyrrolidine, piperidine, morpholine or piperizine group that if necessary can be substituted with (C1-C4)-alkyl; under condition that R2 and R3 don't mean hydrogen atom simultaneously, and to their physiologically acceptable salts and optical isomers. Compounds show inhibitory effect on activity of hormone-sensitivity lipase (HSL). Also, invention describes a method for preparing these compounds.

EFFECT: valuable medicinal and biochemical properties of compounds.

9 cl, 43 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new heterocyclic derivatives having calpain inhibition activity or oxygen reactive form recovering entrapping activity of formula I

1, wherein Het represent monocyclic 5-6-membered hetericyclic radical containing 1-2 heteroatoms selected from O or N; A represents A1

2, A'1 3, A2 4, A3 5 and A4 6; X represent -(CH2)n-, -(CH2)n-CO-, -N(R45)-CO-(CH2)n-CO, -CO-N(R45)-D-CO-, -N(R45)-(CH2)n-CO-, -N(R45)-CO-C(R46R47)-CO-, -O-(CH2)n-CO-, -N(R45)-CO-NH-C(R46R47)-CO-, -CO-N(R45)-C(R46R47)-CO- or -Z-CO Y represents -(CH2)p-, C(R53R54)-(CH2)p-, C(R53R54)-CO-; R1 represents hydrogen, group CR3 or oxo; R3 represents hydrogen, monocyclic saturated 6-membered heterocycloalkylcarbonyl, wherein heterocycle contains two heteroatoms selected from nitrogen or oxygen, C1-C6-alkylcarbonyl, phenylcarbonyl or phenyl(C1-C6)-alkylcarbonyl optionally substituted with NR4R5, or R4 and R5 independently represent C1-C6-alkyl; R2 represents hydrogen, and pharmaceutical compositions containing the same.

EFFECT: new heterocyclic drugs.

18 cl, 37 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

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

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):

wherein Y means lower alkylene; R1 means phenyl with 1 or 2 substitutes taken among group consisting of trihalogen-(lower)-alkyl, halogen atom, lower alkylamino-, di-(lower)-alkylamino- and nitro-group; R2 means phenyl or indolyl and each comprises 1 or 2 substitutes taken among group consisting of lower alkyl, trihalogen-(lower)-alkyl, lower alkylene dioxy-, hydroxy-group, hydroxy-(lower)-alkyl, lower alkoxy- lower alkylamino- and di-(lower)-alkylamino-group; R3 means hydrogen atom; R4 means morpholinyl-(lower)-alkyl comprising 1 or 2 substitutes taken among group consisting of ethyl, hydroxy-(lower)-alkyl, halogen-(lower)-alkyl and lower alkoxy-(lower)-alkyl, or morpholinyl-(lower)-alkynyl that can comprise 1 or 2 substitutes taken among group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo-(lower)-alkyl, lower alkoxy-(lower)-alkyl, hydroxy-(lower)-alkyl, carboxy-(lower)-alkyl, di-(lower)-alkyl-carbamoyl, lower alkoxycarbonyl and halogen-(lower)-alkyl. Also, invention relates to a method for preparing, pharmaceutical composition based on these compounds and a method for treatment of tachykinine-mediated diseases, such as respiratory diseases, ophthalmic, cutaneous, inflammatory diseases, and as analgetic agents. Describes compounds are antagonists of tachykinine.

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

8 cl, 94 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

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