US 2004/0171530 A1 · Somatostatin agonists

Abstract

Claimed are a series of somatostatin agonists typically characterized by alkylation of the amide nitrogen, and uses thereof. Examples of claimed compounds are those according to formula (I), A1-cyclo{Cys-A2-D-Trp-A3-A4-Cys}-A5-Y1, wherein: A1 is an optionally substituted D- or L-aromatic α-amino acid or optionally substituted D- or L-cyclo(C3-6)alkylalanine; A2 is an optionally substituted aromatic α-amino acid or optionally substituted cyclo(C3-6)alkylalanine; A3 is Lys or Orn; A4 is β-Hydroxyvaline, Ser, hSer, or Thr; A5 is β-Hydroxyvaline, Ser, hSer, or Thr, and Y1 is OH, NH2 or NHR1, where R1 is (C1-6) alkyl; wherein each said optionally substituted aromatic α-amino acid and each said optionally substituted cyclo(C3-6) alkylalanine is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NO2, OH, CN, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C1-6)alkoxy, Bzl, O-Bzl, and NR9R10, where R9 and R10 each is independently H or (C1-6) alkyl; and wherein the amine nitrogen of each peptide bond and the amino group of A1 of formula (I) is optionally substituted with a methyl group, provided that there is at least one said methyl group; and further provided that said compound is not D-Phe-cyclo{Cys-Phe-D-Trp-Lys(N-Me-Thr)-Cys}-Thr-NH2; or a pharmaceutically acceptable salt thereof.

Claims43

Dependent claims

A compound of the formula (I),

A1-cyclo{Cys-A2-D-Trp-A3-A4-Cys}-A5-Y1, (I)
wherein:
A1 is an optionally substituted D- or L-aromatic α-amino acid or optionally substituted D- or L-cyclo(C3-6)alkylalanine;
A2 is an optionally substituted aromatic α-amino acid or optionally substituted cyclo(C3-6)alkylalanine;
A3 is Lys or Orn;
A4 is β-Hydroxyvaline, Ser, hSer, or Thr;
A5 is β-Hydroxyvaline, Ser, hSer, or Thr;
and
Y1 is OH, NH2 or NHR1, where R1 is (C1-6)alkyl;
wherein each said optionally substituted aromatic α-amino acid and each said optionally substituted cyclo(C3-6)alkylalanine is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NO2, OH, CN, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C1-6)alkoxy, Bzl, O-Bzl, and NR9R10, where R9 and R10 each is independently H or (C1-6) alkyl;
and
wherein the amine nitrogen of each peptide bond and the amino group of A1 of formula (I) is optionally substituted with a methyl group, provided that there is at least one said methyl group;
and further provided that said compound is not D-Phe-cyclo{Cys-Phe-D-Trp-Lys-(N-Me-Thr)-Cys}-Thr-NH2;
or a pharmaceutically acceptable salt thereof.

11 more elements

A compound selected from the group consisting of:

7 D-β-Nal-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;
D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-β-Nal-NH2;
D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-β-Nal-NH2;
D-β-Nal-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2;
D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-NH2;
D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-OH;
D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-OH;
Gly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OH;
Phe-Pen-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH;
Phe-Pen-Phe-D-Trp-Lys-Thr-Pen-Thr-OH;
H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol;
H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
H-D-Trp-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
H-D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2;
H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
Ac-D-Phe-Lys*-Tyr-D-Trp-Lys-Val-Asp-Thr-NH2 (an amide bridge formed between Lys* and Asp);
Ac-hArg(Et)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(Et)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(Bu)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(Et)2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-L-hArg(Et)2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(CH2CF3)2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2;
Ac-D-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt;
Ac-L-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys(Me)-Thr-Cys-Thr-NH2;
Ac-D-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys(Me)-Thr-Cys-Thr-NHEt;
Ac-hArg(CH3;
hexyl)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
H-hArg(hexyl2)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(Et)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt;
Ac-D-hArg(Et)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2;
Propionyl-D-hArg(Et)2-Gly-Cys-Phe-D-Trp-Lys(ipr)-Thr-Cys-Thr-NH2;
Ac-D-β-Nal-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Gly-hArg(Et)2-NH2;
Ac-D-Lys(iPr)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(CH2CF3)2-D-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-D-hArg(CH2CF3)2-D-hArg(CH2CF3)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2;
Ac-D-hArg(Et)2-D-hArg(Et)2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2;
Ac-Cys-Lys-Asn-4-Cl-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser-D-Cys-NH2;
Bmp-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
Bmp-Tyr-D-Trp-Lys-Val-Cys-Phe-NH2;
Bmp-Tyr-D-Trp-Lys-Val-Cys-p-Cl-Phe-NH2;
Bmp-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH2;
H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;
H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-β-Nal-NH2;
H-pentafluoro-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;
Ac-D-β-Nal-Cys-pentafluoro-Phe-D-Trp-Lys-Val-Cys-Thr-NH2;
H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH2;
H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH2;
H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;
H-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;
Ac-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;
H-D-Phe-Cys-β-Nal-D-Trp-Lys-Val-Cys-Thr-NH2;
H-D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2;
cyclo(Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe);
cyclo(Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe);
cyclo(Pro-Phe-D-Trp-Lys-Thr-N-Me-Phe);
cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Thr-Phe);
cyclo(Pro-Tyr-D-Trp-Lys-Thr-Phe);
cyclo(Pro-Phe-D-Trp-Lys-Thr-Phe);
cyclo(Pro-Phe-L-Trp-Lys-Thr-Phe);
cyclo(Pro-Phe-D-Trp(F)-Lys-Thr-Phe);
cyclo(Pro-Phe-Trp(F)-Lys-Thr-Phe);
cyclo(Pro-Phe-D-Trp-Lys-Ser-Phe);
cyclo(Pro-Phe-D-Trp-Lys-Thr-p-Cl-Phe);
cyclo(D-Ala-N-Me-D-Phe-D-Thr-D-Lys-Trp-D-Phe);
cyclo(D-Ala-N-Me-D-Phe-D-Val-Lys-D-Trp-D-Phe);
cyclo(D-Ala-N-Me-D-Phe-D-Thr-Lys-D-Trp-D-Phe);
cyclo(D-Abu-N-Me-D-Phe-D-Val-Lys-D-Trp-D-Tyr);
cyclo(Pro-Tyr-D-Trp-t-4-AchxAla-Thr-Phe);
cyclo(Pro-Phe-D-Trp-t-4-AchxAla-Thr-Phe);
cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe);
cyclo(N-Me-Ala-Tyr-D-Trp-t-4-AchxAla-Thr-Phe);
cyclo(Pro-Tyr-D-Trp-4-Amphe-Thr-Phe);
cyclo(Pro-Phe-D-Trp-4-Amphe-Thr-Phe);
cyclo(N-Me-Ala-Tyr-D-Trp-4-Amphe-Thr-Phe);
cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba);
cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba-Gaba);
cyclo(Asn-Phe-D-Trp-Lys-Thr-Phe);
cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-NH(CH2)4CO);
cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-β-Ala);
cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-D-Glu)-OH;
cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe);
cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Gly);
cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba);
cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gly);
cyclo(Asn-Phe-Phe-D-Trp(F)-Lys-Thr-Phe-Gaba);
cyclo(Asn-Phe-Phe-D-Trp(NO2)-Lys-Thr-Phe-Gaba);
cyclo(Asn-Phe-Phe-Trp(Br)-Lys-Thr-Phe-Gaba);
cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe(I)-Gaba);
cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Tyr(But)-Gaba);
cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys)-OH;
cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys)-OH;
cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Tpo-Cys)-OH;
cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-MeLeu-Cys)-OH;
cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Phe-Gaba);
cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-D-Phe-Gaba);
cyclo(Phe-Phe-D-Trp(5F)-Lys-Thr-Phe-Phe-Gaba);
cyclo(Asn-Phe-Phe-D-Trp-Lys(Ac)-Thr-Phe-NH—(CH2)3—CO);
cyclo(Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba);
cyclo(Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba);
cyclo(Orn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba);
and H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-NH2;
wherein a disulfide bond exists in the compound having two Cys residues and where the amine nitrogen of each amide peptide bond and the amino group of the N-terminal amino acid is optionally substituted with a methyl group, provided that there is at least one said methyl group in the compound.

106 more elements

A compound of the formula (II),

3
wherein
A1 is a D- or L-isomer of Ala, Leu, Ile, Val, Nle, Thr, Ser, β-Nal, β-Pal, Trp, Phe, 2,4-dichloro-Phe, pentafluoro-Phe, p-X-Phe, or o-X-Phe, wherein X is CH3, Cl, Br, F, OH, OCH3 or NO2;
A2 is Ala, Leu, Ile, Val, Nle, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe, wherein X is CH3, Cl, Br, F, OH, OCH3 or NO2;
A3 is pyridyl-Ala, Trp, Phe, β-Nal, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe, wherein X is CH3, Cl, Br, F, OH, OCH3 or NO2;
A6 is Val, Ala, Leu, Ile, Nle, Thr, Abu, or Ser;
A7 is Ala, Leu, Ile, Val, Nle, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe, wherein X is CH3, Cl, Br, F, OH, OCH3 or NO2;
A8 is a D- or L-isomer of Ala, Leu, Ile, Val, Nle, Thr, Ser, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, p-X-Phe, or o-X-Phe, wherein X is CH3, Cl, Br, F, OH, OCH3 or NO2;
each R1 and R2, independently, is H, lower acyl or lower alkyl;
and R3 is OH or NH2;
provided that at least one of A1 and A8 and one of A2 and A7 must be an aromatic amino acid;
and further provided that A1, A2, A7 and A8 cannot all be aromatic amino acids;
wherein the amine nitrogen of each of the amide peptide bond is optionally substituted with a methyl group provided that there is at least one said methyl group in a compound of formula (II).

10 more elements

Dependencies are inferred from the claim text.

Somatostatin agonists

Life of this patent

Somatostatin agonists

Life of this patent

Abstract

Claims43