US2012129774A1PendingUtilityA1
Kinin b1 receptor peptide agonists and uses thereof
Est. expiryJun 1, 2025(expired)· nominal 20-yr term from priority
C07K 7/18A61P 9/02A61P 3/10A61P 31/08A61P 35/00A61P 9/00A61P 13/12
41
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Claims
Abstract
The present invention provides for novel kinin B 1 receptors peptide agonists of formula (1) having very good to excellent affinities and selectivity for the B 1 receptor, in vitro and in vivo increased resistance to enzymatic degradation, superior pharmacokinetic properties to those of naturally occurring agents, capacity to significantly enhance delivery of chemotherapeutic substances across the blood brain barrier and within peripheral tissues for the treatment of tumors, capacity to protect and restore kidney, heart, brain and other organ functions, when given alone or in combination with other therapies in the treatment of hypertension, diabetes and other cardiovascular diseases particularly, but not limited to, atherosclerosis and arteriosclerosis. aa y -aa x -aa 0 -aa 1 -aa 2 -aa 3 -aa 4 -aa 5 -Ser 6 -Pro 7 -D-Phe 8 -X (1)
Claims
exact text as granted — not AI-modified1 - 20 . (canceled)
21 . A method for reducing the risks of kidney failure due to a lack of tissue perfusion in a patient suffering from diabetes, said method comprising the step of administering to said patient a compound of formula (1)
aa y -aa x -aa 0 -aa 1 -aa 2 -aa 3 -aa 4 -aa 5 -Ser 6 -Pro 7 -D-Phe 8 -X
(1)
or a salt thereof;
wherein:
X is OH or NH 2 ;
aa y is Sar, acetyl or other acyl group;
aa x is L-Arg, D-Arg, L-Lys, D-Lys, L-Orn, D-Orn, another basic amino acid of the L or D-configuration, L-Cit, D-Cit or is absent;
aa 0 is L-Arg, D-Arg, L-Lys, D-Lys, L-Orn, D-Orn, another basic amino acid of the L or D-configuration, or L-Cit, D-Cit;
aa 1 is L-Arg or D-Arg;
aa 2 is L-Pro, L-Oic, another L-Pro mimic amino acid, L-Hyp, L-α-(Me)Pro or another Pro-mimic amino acid derivative chosen from 5,5-dimethylthiazolidine-4-carboxylic acid; 3,4-dehydro-proline; azetidine-2-carboxylic acid; trans-4-cyano-proline; cis-4-cyano-proline; 2-ethylthiazolidine-4-carboxylic acid; thiazolidine-2-carboxylic acid; 2-methylthiazolidine-4-carboxylic acid; and 3-phenylpyrrolidine-2-carboxylic acid;
aa 3 is L-Pro, or another L-Pro-mimic amino acid, L-Hyp, L-Oic, L-α-(Me)Pro or another Pro-mimic amino acid derivative chosen from 5,5-dimethylthiazolidine-4-carboxylic acid; 3,4-dehydro-proline; azetidine-2-carboxylic acid; trans-4-cyano-proline, cis-4-cyano-proline; 2-ethylthiazolidine-4-carboxylic acid; thiazolidine-2-carboxylic acid; 2-methylthiazolidine-4-carboxylic acid; and 3-phenylpyrrolidine-2-carboxylic acid;
aa 4 is Gly, ethyl amine, or Aib,
aa 5 is L-Phe, D-Phe, Acc, L-Cha, D-Cha, L-Chg, D-Chg, L-Cpg, D-Cpg, L-Igl, D-Igl, L-Pen, D-Pen, L-4Bip, D-4Bip, L-Phg, D-Phg, L-Thi, or D-Thi; and
D-Phe 8 is D-Phe. or
-aa 2 -aa 3 -aa 4 - is an aliphatic ω-amino carboxyl residue with a chain length of 8 carbon atoms; and X, aa y , aa x , aa 0 , aa 1 , aa 5 , and D-Phe 8 are as previously defined; or
-aa 2- -aa 3 -aa 4 -aa 5 - is an aliphatic ω-amino carboxyl residue with a chain length of 11 carbon atoms; and X, aa y , aa x , aa 0 , aa 1 , and D-Phe 8 are as previously defined.
22 . The method of claim 21 , wherein said compound is chosen from:
SarArgArgProProGlyPheSerProD-Phe-X
SarD-ArgArgProProGlyPheSerProD-Phe-X
AcArgArgProProGlyPheSerProD-Phe-X
AcD-ArgArgProProGlyPheSerProD-Phe-X
acylArgArgProProGlyPheSerProD-Phe-X
acylD-ArgArgProProGlyPheSerProD-Phe-X
SarArgArgProHypGlyPheSerProD-Phe-X
SarD-ArgArgProHypGlyPheSerProD-Phe-X
AcArgArgProHypGlyPheSerProD-Phe-X
AcD-ArgArgProHypGlyPheSerProD-Phe-X
acylArgArgProHypGlyPheSerProD-Phe-X
acyLD-ArgArgProHypGlyPheSerProD-Phe-X
SarLysArgProHypGlyPheSerProD-Phe-X
SarD-LysArgProHypGlyPheSerProD-Phe-X
AcLysArgProHypGlyPheSerProD-Phe-X
AcD-LysArgProHypGlyPheSerProD-Phe-X
acylLysArgProHypGlyPheSerProD-Phe-X
acylD-LysArgProHypGlyPheSerProD-Phe-X
SarOrnAraProProGlyPheSerProD-Phe-X
SarD-OrnArgProProGlyPheSerProD-Phe-X
acylArgArgArgProProGlyPheSerProD-Phe-X
acyLD-ArgArgArgProProGlyPheSerProD-Phe-X
acylArgD-ArgArgProProGlyPheSerProD-Phe-X
acylD-ArgD-ArgArgProProGlyPheSerProD-Phe-X
SarArgArgArgProProGlyPheSerProD-Phe-X
SarD-ArgArgArgProProGlyPheSerProD-Phe-X
SarArgD-ArgArgProProGlyPheSerProD-Phe-X
SarD-ArgD-ArgArgProProGlyPheSerProD-Phe-X
AcLysLysArgProProGlyPheSerProD-Phe-X
AcD-LysLysArgProProGlyPheSerProD-Phe-X
AcLysD-LysArgProProGlyPheSerProD-Phe-X
AcD-LysD-LysArgProProGlyPheSerProD-Phe-X
SarLysLysArgProProGlyPheSerProD-Phe-X
SarD-LysLysArgProProGlyPheSerProD-Phe-X
SarLysD-LysArgProProGlyPheSerProD-Phe-X
SarD-LysD-LysArgProProGlyPheSerProD-Phe-X
SarLysArgProHypayAccSerProD-Phe-X
SarArgArgProHypGlyAccSerProD-Phe-X
SarLysArgProHypGly4BipSerProDPhe-X
SarArgArgProHypGly4BipSerProD-Phe-X
SarLysArgProHypGlyChaSerProD-Phe-X
SarArgArgProHypGlyChaSerProD-Phe-X
SarLysArgProHypGlyPenSerProD-Phe-X
SarArgArgProHypGlyPenSerProD-Phe-X
SarLysArgProHypGlyThiSerProD-Phe-X
SarArgArgProHypGlyThiSerProD-Phe-X
SarLysArgProHypGlyCpgSerProD-Phe-X
SarArgArgProHypGlyCogSerProD-Phe-X
SarLysArgProHypGlyChgSerProD-Phe-X
SarArgArgProHypGlyChgSerProD-Phe-X
SarLysArgProHypGlyPhgSerProD-Phe-X
SarArgArgProHypGlyPh9SerProD-Phe-X
SarLysArGNH-(CH 2 ) 7 -COPheSerProD-Phe-X
SarArgArgNH-(CH 2 ) 7 -COPheSerProD-Phe-X
AcLysArgNH-(CH 2 ) 7 -COPheSerProD-Phe-X
AcArgArgNH-(CH 2 ) 7 -COPheSerProD-Phe-X
SarOrnArgNH-(CH 2 ) 7 -COPheSerProD-Phe-X
AcOrnArgNH-(CH 2 ) 7 -COPheSerProD-Phe-X
SarLysArgNH-(CH 2 ) 10 -COSerProD-Phe-X
SarArgArgNH-(CH 2 ) 10 -COSerProD-Phe-X
AcLysArgNH-(CH 2 ) 10 -COSerProD-Phe-X
AcArgArgNH-(CH 2 ) 10 -COSerProD-Phe-X
SarOrnArgNH-(CH 2 ) 10 -COSerProD-Phe-X
AcOrnArgNH-(CH 2 ) 10 -COSerProD-Phe-X
SarLysArgProHypGlyIglSerProD-Phe-X
and
SarArgArgProHypGlyIglSerProD-Phe-X.
23 . The method of claim 21 , wherein said compound is chosen from:
SarLysArgProHypGlyChaSerProD-Phe-X
SarLysArgProHypGlyPhgSerProD-Phe-X
SarLysArgProHypGlyIglSerProD-Phe-X
SarLysArgProHypGlyPenSerProD-Phe-X
and
SarLysArgProHypGlyCpgSerProD-Phe-X.
24 . A method for treating peripheral and coronary arterial diseases in a patient in need thereof, said method comprising the step of administering to said patient a compound of formula (1)
aa y -aa x -aa 0 -aa 1 -aa 2 -aa 3 -aa 4 -aa 5 -Ser 6 -Pro 7 -D-Phe 8 -X
(1)
or a salt thereof;
wherein:
X is OH or NH 2 ;
aa y is Sar, acetyl or other acyl group;
aa x is L-Arg, D-Arg, L-Lys, D-Lys, L-Orn, D-Orn, another basic amino acid of the L or D-configuration, L-Cit, D-Cit or is absent;
aa 0 is L-Arg, D-Arg, L-Lys, D-Lys, L-Orn, D-Orn, another basic amino acid of the L or D-configuration, or L-Cit, D-Cit;
aa 1 is L-Arg or D-Arg;
aa 2 is L-Pro, L-Oic, another L-Pro mimic amino acid, L-Hyp, L-α-(Me)Pro or another Pro-mimic amino acid derivative chosen from 5,5-dimethylthiazolidine-4-carboxylic acid; 3,4-dehydro-proline; azetidine-2-carboxylic acid; trans-4-cyano-proline; cis-4-cyano-proline; 2-ethylthiazolidine-4-carboxylic acid; thiazolidine-2-carboxylic acid; 2-methylthiazolidine-4-carboxylic acid; and 3-phenylpyrrolidine-2-carboxylic acid;
aa 3 is L-Pro, or another L-Pro-mimic amino acid, L-Hyp, L-Oic, L-α-(Me)Pro or another Pro-mimic amino acid derivative chosen from 5,5-dimethylthiazolidine-4-carboxylic acid; 3,4-dehydro-proline; azetidine-2-carboxylic acid; trans-4-cyano-proline; cis-4-cyano-proline; 2-ethylthiazolidine-4-carboxylic acid; thiazolidine-2-carboxylic acid; 2-methylthiazolidine-4-carboxylic acid; and 3-phenylpyrrolidine-2-carboxylic acid;
aa 4 is Gly, ethyl amine, or Aib;
aa 5 is L-Phe, D-Phe, Acc, L-Cha, D-Cha, L-Chg, D-Chg, L-Cpg, D-Cpg, L-Igl, D-Igl, L-Pen, D-Pen, L-4Bip, D-4Bip, L-Phg, D-Phg, L-Thi, or D-Thi; and
D-Phe 5 is D-Phe. or
-aa 2 -aa 3 -aa 4 - is an aliphatic ω-amino carboxyl residue with a chain length of 8 carbon atoms; and X, aa y , aa x , aa 0 , aa 1 , aa 5 , and D-Phe 8 are as previously defined; or
-aa 2 -aa 3 -aa 4 -aa 5 - is an aliphatic ω-amino carboxyl residue with a chain length of 11 carbon atoms; and X, aa y , aa x , aa 0 , aa 1 , and D-Phe 8 are as previously defined.
25 . The method of claim 24 , wherein said compound is chosen from:
SarArgArgProProGlyPheSerProD-Phe-X
SarD-ArgArgProProGlyPheSerProD-Phe-X
AcArgArgProProGlyPheSerProD-Phe-X
AcD-ArgArgProProGlyPheSerProD-Phe-X
acylArgArgProProGlyPheSerProD-Phe-X
aloyID-ArgArgProProGlyPheSerProD-Phe-X
SarArgArgProHypGlyPheSerProD-Phe-X
SarD-ArgArgProHypGlyPheSerProD-Phe-X
AcArgArgProHypGlyPheSerProD-Phe-X
AcD-ArgArgProHypGlyPheSerProD-Phe-X
acylArgArgProHypGlyPheSerProD-Phe-X
acylD-ArgArgProHypGlyPheSerProD-Phe-X
SarLysArgProHypGlyPheSerProD-Phe-X
SarD-LysArgProHypGlyPheSerProD-Phe-X
AcLysArgProHypGlyPheSerProD-Phe-X
AclD-LysArgProHypGlyPheSerProD-Phe-X
acylLysArgProHypGlyPheSerProD-Phe-X
acyID-LysArgProHypGlyPheSerProD-Phe-X
SarOrnArgProProGlyPheSerProD-Phe-X
SarD-OrnArgProProGlyPheSerProD-Phe-X
acylArgArgArgProProGlyPheSerProD-Phe-X
acy1D-ArgArgArgProProGlyPheSerProD-Phe-X
acylArgD-ArgArgProProGlyPheSerProD-Phe-X
acylD-ArgD-ArgArgProProGlyPheSerProD-Phe-X
SarArgArgArgProProGlyPheSerProD-Phe-X
SarD-ArgArgArgProProGlyPheSerProD-Phe-X
SayArgD-ArgArgProProGlyPheSerProD-Phe-X
SarD-ArgD-ArgArgProProGlyPheSerProD-Phe-X
AcLysLysArgProProGlyPheSerProD-Phe-X
AcD-LysLysArgProProGlyPheSerProD-Phe-X
AcLysD-LysArgProProGlyPheSerProD-Phe-X
AcD-LysD-LysArgProProGlyPheSerProD-Phe-X
SarLysLysArgProProGlyPheSerPreD-Phe-X
SarD-LysLysArgProProGlyPheSerProD-Phe-X
SarLysD-LysArgProProGlyPheSerProD-Phe-X
SarD-LysD-LysArgProProGlyPheSerProD-Phe-X
SarLysArgProHypGlyAccSerProD-Phe-X
SarArgArgProHypGlyAccSerProD-Phe-X
SarLysArgProHypGly4BipSerProD-Phe-X
SerArgArgProHypGly4BipSerProD-Phe-X
SarLysArgProHypGlyChaSerProD-Phe-X
SarArgArgProHypayChaSerProD-Phe-X
SarLysArgProHypGlyPenSerProD-Phe-X
SarArgArgProHypGlyPenSerProD-Phe-X
SarLyeArgProHypGlyThiSerProD-Phe-X
SerArgArgProHypGlyThiSerProD-Phe-X
SarLysArgProHypGlyCpgSerProD-Phe-X
SarArgArgProHypGlyCpgSerProD-Phe-X
SarLysArgProHypGlyChgSerPreD-Phe-X
SarArgArgProHypGlyChgSerProD-Phe-X
SarLysArgProHypGlyPhgSerProD-Phe-X
SarArgArgProHypGlyPhgSerProD-Phe-X
SarLysArgNH-(CH 2 ) 7 -COPheSerProD-Phe-X
SarArgArgNH-(CH 2 ) 7 -COPheSerProD-Phe-X
AcLysArgNH-(CH 2 ) 7 -COPheSerProD-Phe-X
AcArgArgNH-(CH 2 ) 7 -COPheSerProD-Phe-X
SarOrnArgNH-(CH 2 ) 7 -COPheSerProD-Phe-X
AcOrnArgNH(CH 2 ) 7 -COPheSerProD-Phe-X
SarLysArgNH-(CH 2 ) 10 -COSerProD-Phe-X
SarArgArgNH-(CH 2 ) 10 -COSerProD-Phe-X
AcLysArgNH-(CH 2 ) 10 -COSerProD-Phe-X
AcArgArgNH-(CH 2 ) 10 -COSerProD-Phe-X
SarOrnArgNH-(CH 2 ) 10 -COSerProD-Phe-X
AcOrnArgNH-(CH 2 ) 10 -COSerProD-Phe-X
SarLysArgProHypGlyIglSerProD-Phe-X
and
SarArgArgProllyoGlyIglSerProD-Phe-X.
26 . The method of claim 24 , wherein said compound is chosen from:
SarLysArgProHypGlyChaSerProD-Phe-X
SarLysArgProHypGlyPhgSerProD-Phe-X
SarLysArgProHypGlyIglSerProD-Phe-X
SarLysArgProHypGlyPenSerProD-Phe-X
and
SarLysArgProHypGlyCpgSerProD-Phe-X.
27 . A method for adjunct treatment of coronary diseases with balloon catheter angioplasty, said method comprising the step of administering to a patient in need thereof a compound of formula (1);
aa Y -aa x -aa 0 -aa 1 -aa 2 -aa 3 -aa 4 -aa 5 -Ser 6 -Pro 7 -D-Phe 8 -X
(1)
or a salt thereof;
wherein:
X is OH or NH 2 ;
aa y is Sar, acetyl or other acyl group;
aa x is L-Arg, D-Arg, L-Lys, D-Lys, L-Orn, D-Orn, another basic amino acid of the L or D-configuration, L-Cit, D-Cit or is absent;
aa 0 is L-Arg, D-Arg, L-Lys, D-Lys, L-Orn, D-Orn, another basic amino acid of the L or D-configuration, or L-Cit, D-Cit;
aa 1 is L-Arg or D-Arg;
aa 2 is L-Pro, L-Oic, another L-Pro mimic amino acid, L-Hyp, L-α-(Me)Pro or another Pro-mimic amino acid derivative chosen from 5,5-dimethylthiazolidine-4-carboxylic acid; 3,4-dehydro-proline, azetidine-2-carboxylic acid; trans-4-cyano-proline; cis-4-cyano-proline; 2-ethylthiazolidine-4-carboxylic acid; thiazolidine-2-carboxylic acid; 2-methylthiazolidine-4-carboxylic acid; and 3-phenylpyrrolidine-2-carboxylic acid;
aa 3 is L-Pro, or another L-Pro-mimic amino acid, L-Hyp, L-Oic, L-α-(Me)Pro or another Pro-mimic amino acid derivative chosen from 5,5-dimethylthiazolidine-4-carboxylic acid; 3,4-dehydro-proline; azetidine-2-carboxylic acid; trans-4-cyano-proline; cis-4-cyano-proline; 2-ethylthiazolidine-4-carboxylic acid; thiazolidine-2-carboxylic acid; 2-methylthiazolidine-4-carboxylic acid; and 3-phenylpyrrolidine-2-carboxylic acid;
aa 4 is Gly, ethyl amine, or Aib;
aa 5 is L-Phe, D-Phe, Acc, L-Cha, D-Cha, L-Chg, D-Chg, L-Cpg, D-Cpg, L-Igl, D-Igl, L-Pen, D-Pen, L-4Bip, D-4Bip, L-Phg, D-Phg, L-Thi, or D-Thi; and
D-Phe 8 is D-Phe. or
-aa 2 -aa 3 -aa 4 - is an aliphatic ω-amino carboxyl residue with a chain length of 8 carbon atoms; and X, aa y , aa x , aa 0 , aa 1 , aa 5 , and D-Phe 8 are as previously defined; or
-aa 2 -aa 3 -aa 4 -aa 5 - is an aliphatic ω-amino carboxyl residue with a chain length of 11 carbon atoms; and X, aa y , aa x , aa 0 , aa 1 , and D-Phe 8 are as previously defined.
28 . The method of claim 27 , wherein said compound is chosen from:
SarArgArgProProGlyPheSerProD-Phe-X
SarD-ArgArgProProGlyPheSerProD-Phe-X
AcArgArgProProGlyPheSerProD-Phe-X
AcD-ArgArgProProGlyPheSerProD-Phe-X
acylArgArgProProGlyPheSerProD-Phe-X
acylD-ArgArgProProGlyPheSerProD-Phe-X
SarArgArgProHlypGlyPheSerProD-Phe-X
SarD-ArgArgProHypGlyPheSerProD-Phe-X
AcArgArgProHypGlyPheSerProD-Phe-X
AcD-ArgArgProHypGlyPheSerProD-Phe-X
acylArgArgProHypGlyPheSerProD-Phe-X
acylD-ArgArgProHypGlyPheSerProD-Phe-X
SarLysArgProHypGlyPheSerProD-Phe-X
SaralysArgProHypGlyPheSerProD-Phe-X
AcLysArgProHypGlyPheSerProD-Phe-X
AcD-LysArgProHypayPheSerProD-Phe-X
acylLysArgProHypayPheSerProD-Phe-X
acylD-LysArgProHypGlyPheSerProD-Phe-X
SarOrnArgProProGlyPheSerProD-Phe-X
SarD-OrnArgProProGlyPheSerProD-Phe-X
acylArgArgArgProProGlyPheSerProD-Phe-X
acylD-ArgArgArgProProGlyPheSerProD-Phe-X
acylArgD-ArgArgProProGlyPheSerProD-Phe-X
acylD-Arga-ArgArgProProGlyPheSerProD-Phe-X
SarArgArgArgProProGlyPheSerProD-Phe-X
SarD-ArgArgArgProProGlyPheSerProD-Phe-X
SarArgD-ArgArgProProGlyPheSerProD-Phe-X
SarD-Arga-ArgArgProProGlyPheSerProD-Phe-X
AcLysLysArgProProGlyPheSerProD-Phe-X
AcD-LysLysArgProProGlyPheSerProD-Phe-X
AcLysD-LysArgProProGlyPheSerProD-Phe-X
AcD-LysD-LysArgProProGlyPheSerProD-Phe-X
SarLysLysArgProProGlyPheSerProD-Phe-X
SarD-LysLysArgProProGisePheSerProD-Phe-X
SarLysD-LysArgProProGlyPheSerProD-Phe-X
SarD-LysD-LysArgProProGlyPheSerProDPhe-X
SarLysArgProHypGlyAccSerProD-Phe-X
SarArgArgProHypGlyAccSerProD-Phe-X
SarLysArgProHypGly4BipSerProD-Phe-X
SarArgArgProHypGly4BipSerProD-Phe-X
SarLysArgProHypGlyChaSerProD-Phe-X
SarArgArgProHypGlyChaSerProD-Phe-X
SarLysArgProHypGlyPenSerProD-Phe-X
SarArgArgProHypGlyPenSerProD-Phe-X
SarLysArgProHypGlyThiSerProD-Phe-X
SarArgArgProHypGlyThiSerProD-Phe-X
SarLysArgProHypGlyCpgSerProD-Phe-X
SarArgArgProHypGlyCpgSerProD-Phe-X
SarLysArgProHypGlyChgSerProD-Phe-X
SarArgArgProHypGlyChgSerProD-Phe-X
SarLysArgProHypGlyPhgSerProD-Phe-X
SarArgArgProHypGlyPhgSerProD-Phe-X
SarLysArgNH-(CH 2 ) 7 -COPheSerProD-Phe-X
SarArgArgNH-(CH 2 ) 7 -COPheSerProD-Phe-X
AcLysArgNH-(CH 2 ) 7 -COPheSerProD-Phe-X
AcArgArgNH-(CH 2 ) 7 -COPheSerProD-Phe-X
SarOrnArgNH-(CH 2 ) 7 -COPheSerProD-Phe-X
AcOrnArgNH-(CH 2 ) 7 -COPheSerProD-Phe-X
SarLysArgNH-(CH 2 ) 10 -COSerProD-Phe-X
SarArgArgNH-(CH 2 ) 10 -COSerProD-Phe-X
ActysArgNH-(CH 2 ) 10 -COSerProD-Phe-X
AcArgArgNH-(CH 2 ) 10 -COSerProD-Phe-X
SarOrnArgNH-(CH 2 ) 10 COSerProD-Phe-X
AcOrnArgNH-(CH 2 ) 10 -COSerProD-Phe-X
SarLysArgProHypGlyIgiSerProD-Phe-X
and
SarArgArgProHypGlyIglSerProD-Phe-X
29 . The method of claim 27 , wherein said compound is chosen from:
SarLysArgProHypGlyChaSerProD-Phe-X
SarLysArgProHypGlyPhgSerProD-Phe-X
SarLysArgProHypGlyIglSerProD-Phe-X
SarLysArgProHypGlyPenSerProD-Phe-X
and
SarLysArgProHypGlyCpgSerProD-Phe-X,Join the waitlist — get patent alerts
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