Michael systems as transglutaminase inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to peptide derivatives and peptidomimetics as transglutaminase inhibitors, methods for their preparation, pharmaceutical compositions containing said compounds as well as use of said transglutaminase inhibitors in particular for treatmenting coeliac disease and transglutaminase dependent diseases.

EFFECT: high efficiency of using said compounds.

12 cl, 20 dwg, 2 tbl, 7 ex

 

The text descriptions are given in facsimile form.

1. The peptide or peptidomimetics General formula (I), (II) or (III)

where MS represents a substituted acceptor olefin following structure

E represents the following group-C(=O)-CH2- or-C(=O)-NH-;
m is 0 or 1;
the remains of the Z1, Z2, Z3independently from each other represent the following groups: -H, -CO-(C1-C6alkyl), -CO-R6- - (C3-C10the nitrogen-containing heteroaryl), -COO-(C3-C10heteroaryl), -COO-(C1-C6alkyl), -CO-COO-(C1-C6alkyl), -COO-R8, -CN, -COOH, -CO-NH(C1-C6alkyl), -CO-N(C1-C6alkyl)(C1-C6alkyl), -CO-NR10R11, -CO-NH2, -SO2-R32, -SO2-N(C1-C6alkyl) (C1-C6alkyl), -SO2-NH2, -SO2-OH, -SO2-NH-O-benzyl--SO2-OR62where at least one of the residues Z1, Z2, Z3different from hydrogen;
the remains of the Z1and Z2together may also represent a residue-CO-O-CH2-CH2-,
the remains of the Z2and Z3together may also represent a residue-CO-CH2-CH2-where
Q and Q' independently from each other are a residue side chain of natural amino acids, -CH2-NH-CO-NH2,

Y represents a hydroxyl group; or represents a residue of a peptide containing up to 6 amino acids linked by amide linkages, where Y may include one of the following amino acid analogues


moreover, C-terminal carbonyl function of the specified residue peptide contains a hydroxyl group, an amino group, a C1-C6alkylamino (where the alkyl group may be substituted by-COOH groups), With1-C6alkoxygroup, C1-C6alkyl group, a C1-C10nitrogen-containing heteroaryl group, phenyl-SO2-NH - or phenyl-NH -, and L1is an R57;
X represents hydrogen; and
-NXX' is an amino group, With6-C12Arakelov-carbonylation (which may contain the Deputy-F), 5-(diaminoalkyl)-2-cyclopenten-1 carbylamine, N,N-di(tert-butyloxycarbonyl)amino, C2-C6nitrogen-containing heterocycle

or X' represents hydrogen; and
X represents an acetyl group, a C4allyloxycarbonyl group, piperidinylcarbonyl group, methylisobutylcarbinol group, isoxazolecarboxylic group, phenylsulfonyl (which can include Deputy-OCF3), thienylallylamine, furancarboxylic group, thienylboronic, or a residue of a peptide containing up to 6 am is nakilat, and linked through amide linkages, where X may contain one of the following amino acid analogs

and N is the end of the specified residue peptide contains an amino group,
acetyl group4allyloxycarbonyl group, C6-C12arachidonoylethanolamine,
where the residues R1-R62independently from each other represent the following groups:
-H, cyclo-C3H5, cyclo-C4H7, cyclo-C5H9, cyclo-C6H11, -Ph, -CH2-Ph, -CH3- 2H5- 3H7, -CH(CH3)2- 4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5- (CH3)3- 5H11, -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2- (CH3)2- C2H5, -CH2- (CH3)3, -CH(C2H5)2- 2H4-CH(CH3)2- 6H13- 3H6-CH(CH3)2- 2H4-CH(CH3)-C2H5, -CH(CH3)-C4H9, -CH2-CH(CH3)-C3H7, -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2, -CH 2- (CH3)2-C2H5,- (CH3)2-C3H7,- (CH3)2-CH(CH3)2,-C2H4- (CH3)3, -CH(CH3)- (CH3)3;
and pharmacologically acceptable salts of the above compounds,
with the exception of compounds of General formula (I), where X and X' represent hydrogen and Y represents a hydroxyl group, and compounds, representing the N-i.e. phenylalanyl-[2-(4-etoxycarbonyl-3-butene)glycyl]leucinamide.

2. The peptide or peptidomimetic according to claim 1 the following General formula (IIB)

where the remains of MS, Q, X, X', X" and Y have the same meanings as in claim 1.

3. The peptide or peptidomimetic according to claim 1 the following General formula (IV)

where Q has the same meaning as Q and Q' according to claim 1,
X' and X" are hydrogen, and
Y, X, X', -NXX' and MS have the meanings given in claim 1.

4. The peptide or peptidomimetic according to claim 1 the following General formula (V)

where MS, Q, Q', X, X' and Y have the same meanings as in claim 1.

5. The peptide or peptidomimetic according to claim 1, where MS has the following structure

where Z represents a hydroxy-group, an amino group, a C1-C6alkylamino, C1-C6dialkylamino, C1-C6alkoxygroup, C1 -C6alkyl group, a C3-C10nitrogen-containing heteroaryl group, or-COO-R8.

6. The peptide or peptidomimetic according to claim 1, selected from the group consisting of the following compounds:
methyl ester of Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-valinol-L-Proline-L-leucine (compound 1);
methyl ester of Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-glutaminyl-L-Proline-L-leucine (compound 2);
methyl ester of Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-phenylalanine (compound 3);
methyl ester of Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-methanol}-L-glutaminyl-L-Proline (compound 4);
Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-glutaminyl-L-Proline-L-isopentylamine (compound 5);
methyl ester [(E)-(L)-6-(2-oxopyrrolidin-1-yl)hept-2-addicabadaway acid-1-ethanoyl]-L-valinol-L-Proline (compound 6);
methyl ester of Nα-acetyl-L-asparaginyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-methanol}-L-glutamyl-L-alanyl-L-valine (compound 7);
methyl ester of Nα-acetyl-L-leucinol-glycinyl-L-prolinol-glycinyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl} -L-serinol-L-leucinol-L-valine is-L-isoleucine-glycine (compound 8);
methyl ester of Nα-benzyloxycarbonyl-{(L-7-amino-4-exoect-2-addicabadaway acid]-1-ethanoyl}-L-valinol-L-Proline-leucine (compound 9);
methyl ester of Nα-acetyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-methanol}-L-glutaminyl-L-glutamyl-L-alanine (compound 10);
Nα-acetyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-methanol}-L-glutaminyl-L-glutamylation ester (compound 11);
methyl ester of Nα-acetyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-methanol}-L-phenylalanine-L-Proline-L-leucine (compound 12);
methyl ester of Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-methanol}-L-phenylalanine-L-Proline-L-leucine (compound 13);
methyl ester of Nα-acetyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-methanol}-L-(p-fluoro)phenylalanine-L-Proline-L-leucine (compound 14);
methyl ester of Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-methanol}-L-(p-fluoro)phenylalanine-L-Proline-L-leucine (compound 15);
methyl ester [(E)-(L)-6-(2-oxopyrrolidin-1-yl)hept-2-addicabadaway acid-1-ethanoyl]-L-valinol-L-homopolymer-L-leucine (compound 16);
methyl ester [(E)-(L)-6-(2-oxopyrrolidin-1-yl)hept-2-addicabadaway acid-1-ethanoyl]-L-cyclohexylglycine-L-homopolymer-L-leucine (compound 17);
methyl ester [(E)-(L)-6-(2-ox is a pyrrolidone-1-yl)hept-2-addicabadaway acid-1-ethanoyl]-L-cyclohexylglycine-L-Proline-L-leucine (compound 18);
methyl ester of Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-glutaminyl-L-Proline-L-tyrosine (compound 19);
methyl ester of Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-glutaminyl-L-Proline-L-leucine (compound 20);
methyl ester of Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-leucinol-L-Proline-L-glutamine (compound 21);
methyl ester of Nα-acetyl-{[L-7-amino-4-exoect-2-addicabadaway acid]-1-ethanoyl}-L-glutaminyl-L-Proline-L-leucine (compound 22);
methyl ester of Nα-(5-methylisoxazol-3-carbonyl)-{[L-7-amino-4-exoect-2-addicabadaway acid]-1-isopropanol}-L-valinol-L-Proline-leucine (compound 23);
isopropyl ester of Nα-(2-perbenzoic)-{[L-7-amino-4-exoect-2-addicabadaway acid]-1-methanol}-L-valinol-L-4-ferrocenyl-leucine (compound 24);
methyl ester of Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-phenylalanine-L-Proline-L-leucine (compound 25);
methyl ester of Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}glycinyl-L-Proline-L-leucine (compound 26);
methyl ester of Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-alanyl-L-Proline-L-leucine (Obedinenie 27);
methyl ester of Nα-tert-butyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-glutaminyl-L-Proline-L-leucine (compound 28);
methyl ester of Nα-thiophene-2-carbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-glutaminyl-L-Proline-L-leucine (compound 29);
methyl ester of Nα-furan-3-carbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-glutaminyl-L-Proline-L-leucine (compound 30);
methyl ester of Nα-isoxazol-5-carbonyl-{[(E)-(L)-6-aminoet-3-addicabadaway acid]-1-ethanoyl}-L-glutaminyl-L-Proline-L-leucine (compound 31);
methyl ester of Nα-(5-methyl-isoxazol-3-carbonyl)-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-glutaminyl-L-Proline-L-leucine (compound 33);
methyl ester of Nα-(TRANS-3-(3-thienyl)acryloyl)-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl }-L-glutaminyl-L-Proline-L-leucine (compound 34);
methyl ester of Nα-acetyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-glutaminyl-L-Proline-L-leucine (compound 35);
methyl ester of Nα-(4-triptoreline-benzazolyl)-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl }-L-glutaminyl-L-Proline-L-leucine (compound 36);
methyl ester of Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-cyclohexyl the CIN-L-Proline-L-leucine (compound 37);
methyl ester of Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-valinol-L-homopolymer-L-leucine (compound 38);
ethyl ester of (E)-(S)-6-benzyloxycarbonylamino-6-[3-((R)-2-phenylcarbamoyl-pyrrolidin-1-carbonyl)phenylcarbamoyl]Gex-2-ene acid (compound 39);
isopropyl ether (E)-(S)-6-benzyloxycarbonylamino-6-{1-[(S)-3-carboxy-1-(3-methyl-butylcarbamoyl)propyl]-2-oxo-1,2-dihydro-pyridine-3-ylcarbonyl}Gex-2-railaway acid (compound 40);
methyl ester of Nα-benzyloxycarbonyl-{[(E)-(L)-2-amino-6-methanesulfonyl]Gex-5-enyl}-L-glutaminyl-L-Proline-L-leucine (compound 3.2.1);
methyl ester of Nα-benzyloxycarbonyl-[(E)-(L)-2-amino-6-dimethylsulphamoyl)Gex-5-enyl]-L-glutaminyl-L-Proline-L-leucine (compound 3.2.2);
methyl ester of Nα-benzyloxycarbonyl-[(L)-2-amino-4-(3)-oxo-cyclopent-1-enyl]butyryl-L-glutaminyl-L-Proline-L-leucine (compound 3.2.3);
methyl ester of Nα-benzyloxycarbonyl-[(L)-2-amino-5-(2-oxopiperidin-(3E)-ilidene)]pentanoyl-L-glutaminyl-L-Proline-L-leucine (compound 3.2.4);
methyl ester of Nα-benzyloxycarbonyl-[(E)-(L)-6-aminoet-2-addicabadaway acid]-L-glutaminyl-L-Proline-L-leucine (compound 3.2.5);
methyl ester of Nα-acetyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-pentylamine}-L-glutaminyl-L-aspartyl-L-Proline (compounds is their 3.2.6);
Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-isopropanol}-L-(p-fluoro-phenylalanine)-L-Proline (compound 3.2.7);
Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-benzoyl}-L-phenylalanine-L-homopolymer-L-leucinamide (connection 3.2.8);
methyl ester of Nα-benzyloxycarbonyl-{[(E)-(L)-7-amino-2-exoect-3-addicabadaway acid]-1-ethanoyl}-L-phenylalanine (compound 3.2.9);
methyl ester of Nα-benzyloxycarbonyl-[(Z)-(L)-2-amino-7-exoect-5-addicabadaway acid]-L-glutaminyl-L-Proline-L-leucine (compound 3.2.10);
methyl ester of Nα-benzyloxycarbonyl-[(Z)-(L)-2-amino-6-cyanogens-5-addicabadaway acid]-L-glutaminyl-L-Proline-L-leucine (compound 3.2.11);
Nα-benzyloxycarbonyl-{[(E)-(L)-6-aminoet-2-addicabadaway acid]-1-ethanoyl}-L-valinol-L-(octahedron-2-carboxyl)-L-leucinamide (compound 4.1);
Nα(piperidinyl-4-carbonyl)-{[(E)-(L)-2-amino-6-phenylsulfonyl]Gex-5-enyl}-L-phenylalanine-L-Proline-L-1-cyclopentylmethyl-2-oxo-2-(1H-tetrazol-5-yl)ethylamide (compound 4.2);
Nα-benzyloxycarbonyl-[(E)-(L)-2-amino-6-benzyloxycarbonyl-Gex-5-enyl]-L-valinol-L-propynylbutylcarbamate (connection 4.3);
isopropyl ether (E)-(S)-6-[(S)-1-((S)-2-ethylcarbamate-pyrrolidin-1-carbonyl)-2-methyl-propellerblades]-6-(2-piperidine-4-yl-ethylamino)Gex-2-incarbone the Oh of the acid (compound 5.1);
methyl ester of (S)-2-[((S)-1-{(E)-2R,5S)-2-(4-terbisil)-9-methanesulfonyl-5-[(5-methyl-isoxazol-3-carbonyl)amino]-4-Oksanen-8-enoyl}pyrrolidin-2-carbonyl)amino]-4-methyl-valerianic acid (compound 5.3.b);
isopropyl ether (E)-(6R,9S)-9-benzyloxycarbonylamino-6-[2-(2-ethylcarbamate-octahedron-1-yl)-1-methyl-2-oxoethylidene]-8-oxo-10-feilder-2-onilovoi acid (compound 5.4);
piperidine-4-carbonyl-((E)-(S)-5-benzylmethyl-1-{2-[2-((S)-2-benzylmethylamine-octahedron-1-yl)-2-oxoethylidene]acetyl}-4-enyl)amide (compound 5.6).

7. The use of the peptide or peptidomimetic according to any one of claims 1 to 6 for the treatment or prevention for the disease.

8. Pharmaceutical composition for treatment or prevention of celiac disease, comprising at least one peptide or peptidomimetic according to any one of claims 1 to 6 and/or their pharmacologically acceptable salts and at least one pharmacologically acceptable carrier, excipient or solvent.

9. Pharmaceutical composition for treatment or prevention of celiac disease according to claim 8 in the form of drops, spray to the oral cavity, nasal spray, pills, tablets, film-coated tablets, multilayer tablets, suppositories, gels, ointments, syrups, powders for inhalation, granules, emulsions, dispersions, microcapsules, capsules, powders or solutions for injection.

10. Pharmaceutical composition for treatment is whether the prevention of celiac disease according to claim 8 or 9, suitable for inhalation or for oral, parenteral, dermal, intradermal, intragastric, subcutaneous, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, vnutrivlagalishnogo, intrabuccal, subcutaneous, rectal, subcutaneous, sublingual, local or percutaneous injection.

11. The method of producing peptides or peptidomimetics according to claim 1, in which m=0, has the following synthetic scheme

(0) the provision of glutamic acid,
(1) attach the protective group (PG1 and PG2) on the C - and N-ends glutamic acid,
(2) the restoration of the carboxyl function of the side chain of glutamic acid to aldehyde,
(3) converting the obtained aldehyde in acceptor substituted electrophilic double bond,
(4) removing the protective groups and
(5) the lengthening of the C-end and/or N-Terminus via a peptide fragment or peptidomimetic;
or in accordance with the following synthetic scheme

(1) obtaining secured on the C-end and N-end of the peptide or peptidomimetic containing glutamic acid,
(2) the restoration of the carboxyl function of the side chain of glutamic acid to aldehyde,
(3) converting the obtained aldehyde substituted in the electrophilic acceptor dual link is b, and
(4) optionally removing the protective groups.

12. The method of producing peptides or peptidomimetics according to claim 1, in which m=1, has the following synthetic scheme

(0) the provision of glutamic acid,
(1) attach the protective group (PG1 and PG2) on the C - and N-ends glutamic acid,
(2) the restoration of the carboxyl function of the side chain of glutamic acid to dittography,
(3) converting the terminal carbonyl functional group received dittography in acceptor substituted electrophilic double bond,
(4) removing the protective groups and
(5) the lengthening of the C-end and/or N-Terminus via a peptide fragment or peptidomimetic;
or in accordance with the following synthetic scheme

(1) obtaining secured on the C-end and N-end of the peptide or peptidomimetic containing glutamic acid,
(2) the restoration of the carboxyl function of the side chain of glutamic acid to dittography,
(3) converting the terminal carbonyl functional group received dittography in acceptor substituted electrophilic double bond, and
(4) optionally removing the protective groups.



 

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30 cl, 25 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: in claim described are organic compounds of formula I where radicals are given in description, which are applicable for elimination, prevention or alleviation of one or more symptoms, associated with HCV disorders.

EFFECT: obtaining pharmaceutical composition which possesses inhibiting activity with respect to NS3-4 HCV serinprotease, including formula I compound and pharmaceutically acceptable carrier.

30 cl, 25 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: in claim described are organic compounds of formula I where radicals are given in description, which are applicable for elimination, prevention or alleviation of one or more symptoms, associated with HCV disorders.

EFFECT: obtaining pharmaceutical composition which possesses inhibiting activity with respect to NS3-4 HCV serinprotease, including formula I compound and pharmaceutically acceptable carrier.

30 cl, 25 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of atazanavir sulfate - HIV protease inhibitor.

EFFECT: invention also relates to pharmaceutical compositions which possess antiviral activity with respect to HIV.

19 cl, 5 dwg, 11 tbl, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to methods for producing protease inhibitors, particularly serine protease inhibitors.

EFFECT: producing protease inhibitors applicable for treating HCV infections.

43 cl, 14 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to the area of biotechnology, namely to production of short peptides - stimulators of production of extracellular matrix protein in the skin, and can be used in the medicine. The peptides produced consist of four amino-acid residues that can be used separately or in combination in the method of stimulation of collagen production using fibroblast.

EFFECT: invention provides for effective collagenesis stimulation in fibroblast cells.

25 cl, 3 dwg, 7 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to molecular medicine and a target-directed drug delivery. There are presented new peptide sequences sized 10 or less amino acids containing at least a continuous amino acid sequence D(LPR) which selectively influence on the VEGFR-1 and NRP-1 expressing cells.

EFFECT: target-directed molecules according to the inventions are applicable for treating and diagnosing the neovascular and angiogenic VEGF-associated disorders, such as cancer, obesity, diabetes, asthma, arthritis, cirrhosis and eye diseases.

16 cl, 4 dwg, 2 ex

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