RU2003110960A - NEW DIPEPTIDYLPEPTIDASE IV INHIBITORS AND THEIR APPLICATION FOR REDUCING BLOOD PRESSURE - Google Patents

Claims (18)

1. The use of at least one dipeptidyl peptidase activity inhibitor (DPIV) or DPIV-like enzymes to produce a pharmaceutical composition for lowering blood pressure levels or related disorders in a mammal. 2. The use according to claim 1, where the inhibitor is selected from the group consisting of dipeptide compounds, peptide compounds, including tri-, tetra- and pentapeptides, peptidylketones, aminoketone derivatives, and side chain modified DPIV inhibitors. 3. The use according to any one of the preceding paragraphs, where the dipeptyl peptidase IV-like enzyme is selected from the group consisting of fibroblast-activating protein α, dipeptidyl peptidase IV β, dipeptidyl aminopeptidase-like protein, N-acetylated α-linked acid dipeptidase, latent cell proline- dipeptidases, dipeptidyl peptidases II, attractin and dipeptidyl peptidases IV, related protein (DPP 8), dipeptidyl peptidases 9 (DPP9), DPRP1, DPRP2, DPRP3 or KIAAI492. 4. The use according to any one of the preceding paragraphs, where the structure of the dipeptidyl peptidase IV-like enzyme is unsolved. 5. The use according to any one of claims 1 to 3, wherein the inhibitor is a dipeptide-like compound formed from an amino acid and a thiazolidine or pyrrolidine group and their salts. 6. The use according to claim 5, where the dipeptide compound is selected from the group consisting of L-threo-isoleucyl pyrrolidine, L-allo-isoleucylthiazolidine, L-threo-isoleucylpyrrolidine, L-allo-isoleucylpyrrolidine, L-glutaminylthiarolidine, L-glutaminylthiarolidine, L-glutaminylthiarolidine, L-glutaminylthiarolidine, L-glutaminylthiarolidine, L-glutamic acid-thiazolidine, L-glutamic acid-pyrrolidine, alanylpyrrolidine, N-valyl prolyl-O-benzoylhydroxylamine and their salts. 7. The use according to any one of claims 1 to 3, wherein the inhibitor is a peptide compound used to competitively modulate catalysis with dipeptidyl peptidase IV, represented by the general formula

where A is an amino acid other than a D-amino acid; B is an amino acid selected from Pro, Ala, Ser, Gly, Hyp, azetidine- (2) -carboxylic acid and pipecolinic acid, C is any acid other than Pro, Hyp, azetidine- (2) -carboxylic acid, pipecolic acid and in addition to N-alkyl amino acids, for example, N-methylvaline and sarcosine, D represents any amino acid or is absent, and E is any amino acid or is absent, or C is any amino acid except Pro, Hyp, azetidine- (2) -carboxylic acid, pipecolic acid, except for N-alkyl amino acids, for example, N-methylvaline and sarcosine, and in addition to D-amino acid; D is any amino acid selected from Pro, Ala, Ser, Gly, Hyp, azetidine- (2) -carboxylic acid and pipecolinic acid, and E is any amino acid except Pro, Hyp, azetidine- (2) -carboxylic acid, pipecolinic acid and in addition to N-alkylated amino acids, for example N-methylvaline and sarcosine. 8. The use according to any one of claims 1 to 3, wherein the inhibitor is a peptidyl ketone represented by the general formula

including all stereoisomers, and pharmaceutically acceptable salts thereof, where A is selected from

X ¹ represents H or an acyl or hydroxycarbonyl group or an amino acid or peptide residue, X ² represents H, - (CH) _n —NH — C ₅ H ₃ NY cn = 2-4 or C ₅ H ₃ NY (divalent pyridyl residue) and Y is selected from H, Br, Cl, I, NO ₂ or CN X ³ represents H or phenyl or pyridyl unsubstituted or substituted by one, two or more alkyl, alkoxy, halogen, nitro, cyano or carboxy groups, X ⁴ represents H or phenyl or pyridyl unsubstituted or substituted by one, two or more alkyl, alkoxy, halo nitro, cyano or carboxy groups, X ⁵ represents H or alkyl, alkoxy or phenyl, X ⁶ represents H or alkyl; for n = 1 X is selected from: H, OR ² , SR ² , NR ² R ³ , N ⁺ R ² R ³ R ⁴ , where R ² means acyl residues that are unsubstituted or substituted by one, two or more alkyl, cycloalkyl, aryl or heteroaryl residues, or means all amino acids and peptide residues, or alkyl residues that are unsubstituted or substituted by one, two or more alkyls, cycloalkyls, aryl and heteroaryl residues, R ³ denotes alkyl and acyl functions, where R ² and R ³ may be part of one or more ring structures of saturated and unsaturated carbocyclic or heterocyclic structures, R ⁴ means alkyl residues, where R ² and R ⁴ or R ³ and R ⁴ may be part of one or more ring structures of saturated and unsaturated carbocyclic or heterocyclic structures; for n = 0 X is selected from

where B is O, S, NR ⁵ , where R ⁵ is H, alkylidene or acyl, C, D, E, F, G, H are independently selected from unsubstituted and substituted alkyls, hydroxyalkyls, thioalkyls, aminoalkyls, carbonylalkyls, acyls, carbamoyl, aryl, and heteroaryl residues; and for n = 0 and n = 1 Z is selected from H, or branched or single C ₁ -C ₉ alkyl or branched or single C ₂ -C ₉ alkenyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₇ cycloalkenyl, aryl or heteroaryl residue, or a side chain selected from all side chains from all natural amino acids or their derivatives. 9. The use according to any one of claims 1 to 3, where the inhibitor is a derivative of the aminoketone represented by the general formulas 5, 6, 7, 8, 9, 10, and 11, including all stereoisomers, and their pharmaceutically acceptable salts,

where R ¹ represents H, a branched or straight C ₁ -C ₉ alkyl residue, a branched or straight C ₂ -C ₉ alkenyl radical, a C ₃ -C ₈ cycloalkyl-, C ₅ -C ₇ cycloalkenyl-, aryl or heteroaryl radical or a side chain of a natural amino acid or derivative thereof; R ³ and R ^{4 are} independently selected from H, hydroxy, alkyl, alkoxy, aryloxy, nitro, cyano or halogen, A represents H or an isoster carboxylic acid, a functional group selected from CN , SO ₃ H, CONHOH, PO ₃ R ⁵ R ⁶ , tetrazole, amide, ester, anhydride, thiazole and imidazole; B is selected from:

where R ⁵ represents H, - (CH) _n -NH-C ₅ H ₃ NY cn = 2-4 and C ₅ H ₃ NY (divalent pyridyl residue) with Y = H, Br, Cl, I, NO ₂ or CN R ¹⁰ represents H, acyl, hydroxycarbonyl or an amino acid residue W represents H or phenyl or pyridyl unsubstituted or substituted by one, two or more alkyl, alkoxy, halogen, nitro, cyano or carboxy groups, W ¹ represents H, alkyl, alkoxy or phenyl, Z represents H or phenyl or pyridyl unsubstituted or substituted by one, two or more alkyl, alkoxy, halogen, nitro, cyano or carboxy groups, Z ’is H or alkyl, D represents a cyclic C ₄ -C ₇ alkyl, C ₄ -C ₇ alkenyl radical, which may be unsubstituted or substituted by one, two or more alkyl groups, or a cyclic (4-7)-membered heteroalkyl or cyclic (4-7) a membered heteroalkenyl residue, X ² represents O, NR ⁶ , N ⁺ (R ⁷ ) ₂ or S, X ³ to X ^{12 are} independently selected from CH ₂ , CR ⁸ R ⁹ , NR ⁶ , N ⁺ (R ⁷ ) ₂ , O, S, SO, and SO ₂ , including all saturated and unsaturated structures, R ⁶ , R ⁷ , R ⁸ , R ^{9 are} independently selected from H, a branched or straight C ₁ -C ₉ alkyl radical, a branched or straight C ₂ -C ₉ alkenyl radical, a C ₃ -C ₈ cycloalkyl radical, C ₅ -C ₇ cycloalkenyl residue, aryl or heteroaryl residue, under the following conditions: Formula 6: X ⁶ represents CH, if A is not H, Formula 7: X ¹⁰ represents C, if A is not H, Formula 8: X ⁷ represents CH, if A is not H, Formula 9: X ¹² represents C, if A is not H, 10. The use according to any one of claims 1 to 3, wherein the inhibitor of the activity of DPIV or DPIV-like enzymes is represented by the general formula

including all stereoisomers and their pharmaceutically acceptable salts, where A represents an amino acid having at least one functional group in the side chain, B is a chemical compound covalently linked to at least one functional group of side chain A, in particular an oligopeptide having a chain length of up to 20 amino acids, or polyethylene glycol having a molar mass of up to 20,000 g / mol, an optionally substituted organic amine , amide, alcohol, acid or aromatic compound having from 8 to 50 C atoms, and C represents thiazolidine, pyrrolidine, cyanopyrrolidine, hydroxyproline, a dehydroproline or a piperidine group linked to A via an amide bond. 11. The use of claim 10, where A represents an amino acid, preferably an α-amino acid, especially a natural α-amino acid having at least one functional group in the side chain selected from the group consisting of threonine, tyrosine, serine, arginine , lysine, aspartic acid, glutamic acid or cysteine. 12. The use according to any one of the preceding paragraphs, wherein said inhibitor is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of said inhibitor or a pharmaceutically acceptable acid addition salt thereof. 13. The use according to any one of the preceding paragraphs, where the inhibitor (s) are used in combination with a pharmaceutically acceptable carrier and / or diluent. 14. The use according to any one of the preceding paragraphs, where at least one of the specified inhibitor is administered repeatedly. 15. The use according to any one of the preceding paragraphs, where the mammal shows clinically inappropriate basal and post-dinner hyperglycemia or blood pressure levels, or both. 16. The use according to any one of the preceding paragraphs for the prevention or alleviation of pathological metabolic abnormalities in mammals, such as glucosuria, hyperlipidemia, metabolic acidosis and diabetes mellitus, leading to a decrease in blood pressure. 17. The use according to any one of the preceding paragraphs to lower blood pressure levels in mammals having a blood pressure of more than 140 mm Hg, where at least one inhibitor is administered periodically. 18. The use according to any one of the preceding paragraphs, including the oral administration of at least one inhibitor or pharmaceutical composition based on it.