Inhibitors of enzyme that converts 1-interleukin

 

The invention relates to compounds of General formulaand-where n = 0, 1, or 2, m and m' = 1 or 2; R11isorR2'= R2= H, R3is-CH2Ar or 5-15 membered non-aromatic monocyclic group which may contain from 0 to 2 endocycles nitrogen atoms; R4is a branched (C1-5) alkyl group; R5choose from a group comprising-C(O)R7, -C(O)OR9, -C(O)C(O)R7; R7selected from the group: phenyl, naphthyl, isoquinoline, and phenyl may be substituted with halogen, (C1-6) alkoxy, 1,2-methylenedioxy or - N(H)C(O)(C1-6)-alkyl, R9independently selected from straight line (C1-5) alkyl group, optionally substituted by phenyl; R12and R13independently selected from the group comprising-R7-C(O)-R7and-C(O)-N(H)-R7or R12and R13together form a 4-8-membered saturated cyclic group, a pharmaceutical composition for the inhibition of enzyme that converts 1-interleukin (ICE), the method of inhibiting the activity IC is

Description text in facsimile form (see the graphical part of) The

Claims

1. The compound represented by formula
where n = 0, 1, or 2;
R11is

or

m = 1 or 2;
R12and R13independently selected from the group comprising-R7, -C(O)-R7and-C(O)-N(H)-R7or R12and R13together form a 4-8-membered saturated cyclic group;
R2is-H;
R7selected from the group comprising phenyl, naphthyl and ethenolysis, where phenyl optionally substituted with halogen, (C1-6) alkoxy, 1,2-methylenedioxy or-N(H)C(O) (C1-6) alkyl;
R5choose their group comprising-C(O)-R7, -C(O)-OR9and-C(O)C(O)-R7;
each AG is a cyclic group independently selected from the group comprising phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulene, fluorene and anthracene, and heterocyclic aromatic group selected from the group comprising 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazoline, pyrazolidine, isoxazole, isothiazolines, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b] furanyl, benzo[b] thiophenyl, 1H-indazole, benzimidazole, benzthiazole, purinol, 4H-hemolysins, chinoline, 1,2,3,4-tetrahydroisoquinoline, ethenolysis, 1,2,3,4-tetrahydroisoquinoline, cannoli, phthalazine, hintline, honokalani, 1,8-naphthyridine, pteridine, carbazole, acridine, phenazine, phenothiazinyl and phenoxazines, and the said aromatic group is optionally substituted by one or more-F, -CL, -Br, -I, -OR14, -NO2, -S(O)2-N(R9)(R10), -C(O)-NR9(R10), -N(H)-C(O)-N(R9)(R10),
-N(R9)(R10), -C(O)-OR9, -CF3, -F3, straight or branched (C1-6) alkyl group, 1,2-methylenedioxy, -CN, or-N(H)C(NR9)N(R9) (R10);
each R14is-H or a straight or branched (C1-6) alkyl group;
each R9independently selected from a direct (C1-5) alkyl group, optionally substituted by phenyl;
each R10independently selected from the group comprising-H, -AG, and straight or branched (C1-5) alkyl group, optionally substituted-AG;
each R4is a branched (C1-5) alkyl group;
R3the beach is 2 endocycles nitrogen atoms, and where the monocyclic group is optionally condensed with Hypertension;
provided that if the AG is substituted by a group containing R9or R10that contains one or more of AG groups,- AG group is not substituted by a group containing R9or R10.

2. Connection on p. 1, where R5is-C(O)-R7or-C(O)C(O)-R7; each R4is a branched (C1-5) alkyl group; m = 1; n = 1; R3is-CH2AG or

E is CH or N; each D is independently N or C, where C is optional substituted-OR14, -F, -Cl, -Br, -I, -NO2, -S(O)2-N(R9)(R10), -C(O)-N(R9)(R10), -N(H)-C(O)-N(R9)(R10), -N(R9)(R10), -C(O)-OR9, -CF3, -F3, straight or branched (C1-6) alkyl group, 1,2-methylenedioxy, -CN, or-N(H)C(NR9)N(R9)(R10); each R9independently selected from a direct (C1-5) alkyl group, optionally substituted by phenyl; and each of R10independently selected from the group comprising-H, -AG, and straight or branched (C1-5) alkyl group, optionally substituted-Ah.

3. The compound represented by the formula


where Y is 0;
each AG is a cyclic group independently selected from the group including a carbocyclic aromatic group selected from the group comprising phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulene, fluorene and anthracene, and heterocyclic aromatic group selected from the group comprising 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazoline, pyrazolidine, isoxazole, isothiazole, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-tritional, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b] furanyl, benzo[b] thiophenyl thinline, 1,2,3,4-tetrahydroisoquinoline, cinnoline, phthalazine, hintline, honokalani, 1,8-naphthyridine, pteridine, carbazole, acridine, phenazine, phenothiazinyl and phenoxazines, and the said cyclic group optionally substituted by one or more OR14, -F, -Cl, -Br, -I, -NO2, -S(O)2-N(R9)(R10), -C(O)-N(R9)(R10), -N(H)-C(O)-N(R9)(R10), -N(R9)(R10), -C(O)-OR9, -CF3, -F3, straight or branched (C1-6) alkyl group, 1,2-methylenedioxy, -CN, or-N(H)C(NR9)N(N9)(R10);
each R9independently selected from straight line (C1-5) alkyl group, optionally substituted by phenyl;
each R10independently selected from the group comprising-H, -AG, and straight or branched(C1-5) alkyl group, optionally substituted AG;
each R14is-H or a straight or branched (C1-6) alkyl group;
R5choose from a group comprising-C(O)-R7, -C(O)-OR9and-C(O)C(O)-R7;
R4is a branched(C1-5) alkyl group;
R3is-CH2AG or 5-15 membered non-aromatic monocyclic group which optionally contains from 0 to 2 endocycles atoms azo what if-AG substituted group, containing R9or R10that contains one or more of AG groups,- AG group is not substituted by a group containing R9or R10.

4. Connection on p. 3, where R1is-C(O)-N; R5is-C(O)-R7or-C(O)C(O)-R7; R4is a branched(C1-5) alkyl group; m = 1; n = 1; R3is-CH2AG or

E is CH or N; each D is independently N or C, where C is optional substituted-OR14, -F, -Cl, -Br, -I, -NO2, -S(O)2-N(R9)(R10), -C(O)N(R9)(R10), -N(H)-C(O)-N(R9)(R10), -N(R9)(R10), -C(O)-OR9, -CF3, -F3, straight or branched (C1-6) alkyl group, 1,2-methylenedioxy, -CN, or-N(H)C(R9)N(K9)(R10); each R9independently selected from a direct (C1-5) alkyl group, optionally substituted by phenyl; each R10independently selected from the group comprising-H, -AG, and branched or straight -(C1-5) alkyl group optionally substituted-Ah.

5. Connection on p. 4, selected from the group including














and

6. Connection on p. 3, where R1is-C(O)-R8; R5is-C(O)-R7or-C(O)C(O)-R7; R4is a branched(C1-5) alkyl group, optionally substituted-AG; m = 1; n = 1;
R3is-CH2AG or

E is CH or N; each D is independently N or C, where C is optional substituted-OR14, -F, -Cl, -Br, -I, -NO2, -S(O)2-N(R9)(R10), -C(O)-N(R9)(R10), -N(H)-C(O)-N(R9)(R10), -N(R9)(R10), -C(O)-OR9, -CF3, -F3, straight or branched (C1-6) alkyl group, 1,2-methylenedioxy, -CN, or-N(H)C(NR9)N(R9)(R10); each R9independently selected from a direct -(C1-5) alkyl group, optionally substituted-AG; and each of R10independently selected from the group, enabling the s on p. 6, selected from the group including









8. Pharmaceutical composition for inhibiting the enzyme that converts 1-interleukin (SE), containing an effective amount of a compound according to any one of paragraphs. 1-7 and a pharmaceutically acceptable carrier.

9. A method of inhibiting the activity SE, including the stage of introduction of the patient connection according to any one of paragraphs. 1-7 or pharmaceutical compositions under item 8.

10. The method of treatment or prevention 1L-1-mediated diseases, including stage injection to a patient compounds according to any one of paragraphs. 1-7 or pharmaceutical compositions under item 8.

11. Method for the treatment or prevention of diseases selected from the group comprising inflammatory diseases, autoimmune diseases, proliferative disorders, infectious diseases, degenerative diseases, necrotic diseases, osteoarthritis, pancreatitis, asthma, respiratory difrancesco thyroiditis, graves ' disease, autoimmune gastritis, insulin-dependent diabetes mellitus (type 1), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, rejection of the transplant, osteoporosis associated with multiple myeloma bone disorders, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and shigellosis patients, including stage of introduction of a given patient the compound according to any one of paragraphs. 1-7 or pharmaceutical compositions under item 8.

12. Method for the treatment or prevention of apoptosis-mediasound diseases including stage injection to a patient compounds according to any one of paragraphs. 1-7 or pharmaceutical compositions under item 8.

13. Method for the treatment or prevention of diseases selected from the group comprising Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, atrophy of the spinal muscles, multiple sclerosis, AIDS-related encephalitis, HIV-related encephalitis, aging, alopecia, and neurological damage as a result of kick the PA is oppozitsii by p. 8.

14. The method according to any of paragraphs. 10-13, where the disease is osteoarthritis, pancreatitis, asthma, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, rejection of the graft or septic shock.

 

Same patents:

The invention relates to the compounds of formula I or formula II, where R1denotes N(R10)(R11); R2means thio-lower alkyl; each of R3and R5independently represents CH2or C(O); R4denotes a substituted or unsubstituted dionissia alkyl, where the Deputy is CH2NHC(O)R13and he added to the specified tighrope; R6denotes the residue synthetic heteroaromatic-amino acids; R7denotes a residue of natural or synthetic-amino acids; R8IT denotes or lower alkoxy, or together with R7forms homoserine; R9denotes H; each of R10and R11, independently, is H; R12denotes a substituted or unsubstituted fragment selected from aryl, allyssia of alkyl, where the substituents are one or more lower Akilov or halogen; R13denotes lower alkyl; R18denotes H; provided that if R4denotes unsubstituted dionissia alkyl, available tigraphy of R2and R4can form a disulfide bond; or pharmaceutically acceptable salts

The invention relates to new compounds of General formula 1: R1- SO2- B - X - Z - C(O) - Y, where R1represents a (1-12C)alkyl, which optionally may be substituted CF3, (7-15C)aralkyl or Campari; represents a bond, an amino acid of formula-NH-CH[(CH2)pC(O)OH]-C(O)-, where R = 1, 2, or 3, D-3-Tiq, or L - or D-amino acid containing a hydrophobic or neutral side chain; X represents an amino acid with a hydrophobic side chain, glutamine, cyclic amino, -NR2-CH2-C(O) -, or a group:

< / BR>
where n = 2, 3 or 4, W represents CH; R3represents H, (1-6C)alkyl; Z represents a lysine or 4-aminocyclohexanol; Y represents-NH-(1-6C)alkylene-C6H5, -OR4where R4represents H, (2-6C)alkyl, or NR5R6and R5and R6independently represent H, (1-6C)alkoxy or (1-6C)alkyl, optionally substituted with halogen, or R5and R6together represent a (3-6C)alkylene, or R5and R6together with the nitrogen atom to which they are attached, represent< / BR>
where V carts is naphthyl-SO2-Asp-Pro-Lys[COCO]-OH,having anticoagulant activity; and the pharmaceutical composition having inhibitory by combinationally

The invention relates to a series peptidergic heterocyclic compounds, intermediates used in their receiving and containing pharmaceutical compositions

The invention relates to new derivatives of Proline, and more specifically to individual forms new derivative of 1-substituted N-[2-methyl-1-(TRIFLUOROACETYL)- propyl]pyrrolidin-2-carboxamide, which are inhibitors of elastase of human leukocytes (ALC), also known as elastase human neutrophils (ANC), which are important, for example, as a means of research work in pharmacological, diagnostic and related studies and in the treatment of diseases of mammals, which also involved ALC

The invention relates to medicine, namely to methods of producing biologically active substances that have immunoregulatory properties, and may find application in medicine, veterinary medicine and experimental biochemistry

The invention relates to amino acid derivatives of the formula I

< / BR>
or its non-toxic salt or its hydrate, the pharmaceutical composition having inhibitory effect on calcium channel iv-type; the inhibitor calcium channel N-type; a pharmaceutical composition for prevention and/or treatment of cerebral infarction and pharmaceutical compositions for the treatment of pain

The invention relates to derivatives of esters of N-alkylacrylate, including their salt form, is represented by the formula (1), the values of the radicals given in the claims

The invention relates to a new compound - tritium-labeled tartino and method for determining taphrina in biological samples, including the introduction of pre in the sample vysokobarnogo tritium captina, extraction, transformation into the prepared extract captina and its labeled analog in them benzoic or ortho-derivative, which is then analyzed by HPLC with fluorescence detection

The invention relates to a sweetener composition containing granules or crystalline powder aspartame and crystals or crystalline powder, Acesulfame-K as the active ingredients, in which the number of Acesulfame-K is 5-90 wt.% the total weight of both components, and the size of the particles of both components is between 20 and 500 μm, while the dissolution rate of the mixture exceeds the rate of dissolution of only one aspartame

The invention relates to granular sweetener, which are granules of a mixture of aspartame and Acesulfame-K as the active ingredients, in which the number of Acesulfame-K is 20-90 wt.% the total weight of both components, and the maximum grain size is 1400 μm or less

The invention relates to a group of compounds of General formula (I) high degree of purification

The invention relates to a derivative of D-Proline General formula

< / BR>
or

< / BR>
where R is SH, benzyl or phenyl, optionally substituted by a hydroxy-group or a lower alkoxygroup, or a group of the formula

< / BR>
R1is hydrogen or halogen; X represents -(CH2)n-; -CH(R2)(CH2)n-; -CH2O(CH2)n-; CH2NH-; benzyl, -C(R2)=CH-; CH2CH (OH)- or thiazol-2,5-diyl; Y represents-S -; (CH2)n; -O-; -NH-; -N (R2)-; -CH=CH-; -NHC(O)NH-; -N(R2)C(O)N(R2)-; -N[CH2WITH6H3(OCH3)2]-; -N(CH2WITH6H5)-; -N(CH2WITH6H5)C(O)N(CH2WITH6H5)-; -N(alkoxyalkyl)-; -N(cyclooctylmethyl)-; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl or diphenylene; 1,2-phenylene; 1,3-phenylene or 1,4-phenylene, where phenylenebis group optionally substituted by 1-4 substituents selected from the group comprising halogen, lower alkyl, lower alkoxygroup, the hydroxy-group, carboxypropyl, -COO-lower thiazolyl, 2-oxo[1,2,3,5] oxadiazolyl, 5-thioxo[1,2,4]oxadiazolyl and 5-tert-butylsulfonyl[1,2,4] oxadiazolyl; X' represents -(CH2)n-; (CH2)nCH(R2)-; -(CH2)nOCH2-; -NHCH2-; benzyl, -CH= C(R2)-; -CH(OH)CH2or thiazol-2,5-diyl; R2denotes lower alkyl, lower alkoxygroup or benzyl and n = 0-3, their pharmaceutically acceptable salts, mono - and diesters, except (R)-1-[(R)- and (R)-1-[(S)-3-mercapto-2-methylpropionyl] pyrrolidin-2-carboxylic acid; medicinal product with amyloidoses activity, and the method of obtaining these derivatives

The invention relates to the compounds of formula I or formula II, where R1denotes N(R10)(R11); R2means thio-lower alkyl; each of R3and R5independently represents CH2or C(O); R4denotes a substituted or unsubstituted dionissia alkyl, where the Deputy is CH2NHC(O)R13and he added to the specified tighrope; R6denotes the residue synthetic heteroaromatic-amino acids; R7denotes a residue of natural or synthetic-amino acids; R8IT denotes or lower alkoxy, or together with R7forms homoserine; R9denotes H; each of R10and R11, independently, is H; R12denotes a substituted or unsubstituted fragment selected from aryl, allyssia of alkyl, where the substituents are one or more lower Akilov or halogen; R13denotes lower alkyl; R18denotes H; provided that if R4denotes unsubstituted dionissia alkyl, available tigraphy of R2and R4can form a disulfide bond; or pharmaceutically acceptable salts

The invention relates to a new group of individual compounds of the formula I

< / BR>
where R denotes optionally substituted aryl, aryl(ness.)alkyl, (ness.)alkenyl, (ness.)quinil or N-containing heterocyclyl; R2and R3each independently of one another denotes hydrogen or optionally substituted (ness.)alkyl, aryl(ness.)alkyl, cycloalkyl(ness.)alkyl, or R2and R3together denote (NISS

The invention relates to new compounds of General formula I

< / BR>
where a is Gly; the remainder of the formula II

< / BR>
m= 0 or 1; n= 2 or 3; R1and R2each independently of the other represents H, R1and R2both together represent also

< / BR>
or

< / BR>
where IS -(CO)-(CH2)q-(CO)rwhere q=1, 2, or 3, r=0 or 1, or-CO-CH=CH-CO-; X IS H, Cl or1-C6alkyl; and if the mean remains optically active amino acids and derivatives of amino acids, are included as D-and L-forms, and their salts, process for the preparation of compounds of formula I and their salts; pharmaceutical composition having the ability to inhibit integrin containing in its structure at least one compound of the formula I and/or one of its physiologically acceptable salts

The invention relates to the field of medicine and for the preparation of Bresolin drops nasal 0.06% and 0.1% for the treatment of diseases of the nose and throat
Up!