Exendin-4 derivatives as dual GLP1/glucagon agonists

Patent metadata

Field	Value
Publication number	US-9365632-B2
Application number	US-201314049597-A
Country	US
Kind code	B2
Filing date	Oct 9, 2013
Priority date	Oct 9, 2012
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

Abstract

The present invention relates to exendin-4 derivatives and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as reduction of excess food intake.

First claim

The invention claimed is:

1. A peptidic compound having formula (I):
R 1 —Z—R 2   (I)

or a salt, or solvate thereof,
wherein Z is a peptide moiety having formula (II)
His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln X14-X15-X16-X17-X18-Ala-X20-X21-Phe-Ile-Glu-Trp-Leu-Lys-X28-X29-Gly-Pro-Ser-Ser-Gly-X35-Pro-Pro-Pro-X39-X40  (II)

wherein
X2 is an amino acid residue selected from Ser, D-Ser, or Aib,
X3 is an amino acid residue selected from Gln, His, and α-amino-functionalized Gln, wherein Gln is optionally functionalized in that an H of the α-amino group is substituted by (C 1 -C 4 )-alkyl,
X14 is an amino acid residue having a side chain with a functionalized —NH 2 group, wherein the functionalized —NH 2 side chain group is functionalized by —C(O)—R 5 , —C(O)O—R 5 , —C(O)NH—R 5 , —S(O) 2 —R 5 or —R 5 , wherein R 5 is a moiety up to 100 carbon atoms and optionally heteroatoms independently selected from halogen, N, O, S, P and combinations thereof,
X15 is an amino acid residue selected from Glu and Asp,
X16 is an amino acid residue selected from Ser, Glu, and Lys,
X17 is an amino acid residue selected from Arg, Glu, Gln, Leu, Aib, and Lys,
X18 is an amino acid residue selected from Arg, Ala, and Lys,
X20 is an amino acid residue selected from Gln, Arg, Lys, His, Glu, and Aib,
X21 is an amino acid residue selected from Asp, Leu, and Glu,
X28 is an amino acid residue selected from Asn, Arg, Lys, Aib, Ser, Glu, Ala, and Asp,
X29 is an amino acid residue selected from Gly, Ala, D-Ala, and Thr,
X35 is an amino acid residue selected from Ala, Glu, Arg, and Lys,
X39 is Ser or is absent, and
X40 is absent or is an amino acid residue having a side chain with an —NH 2 group, wherein the —NH 2 side chain group is optionally functionalized by —C(O)—R 5 , —C(O)O—R 5 , —C(O)NH—R 5 , —S(O) 2 —R 5 or —R 5 , wherein R 5 is a moiety comprising up to 100 carbon atoms and optionally heteroatoms independently selected from halogen, N, O, S, P and combinations thereof,
R 1 is the N-terminal group of the peptidic compound and is selected from —NH 2 or mono- or bisfunctionalized NH 2 ,
wherein the mono- or bisfunctionalized NH 2 is selected from the group consisting of —NH[(C 1 -C 5 )alkyl], —N[(C 1 -C 5 )alkyl] 2 , —NH[(C 0 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl], —NH—C(O)—H, —NH—C(O)—(C 1 -C 5 )-alkyl, and —NH—C(O)—(C 0 -C 3 )alkylene-(C 3 -C 8 )cycloalkyl, in which alkyl or cycloalkyl is unsubstituted or up to 5-fold substituted by —OH or halogen selected from F, CI, Br, and I,

R 2 is the C-terminal group of the peptidic compound and is selected from
(i) —OH and functionalized —OH,
wherein the functionalized —OH is selected from —O—(C 1 -C 20 )alkyl and —O(C 0 -C 8 )alkylene-(C 3 -C 8 )cycloalkyl, or

(ii) —NH 2 or mono- or bisfunctionalized NH 2 ,
wherein the mono- or bisfunctionalized NH 2 is selected from the group consisting of —NH[(C 1 -C 30 )alkyl], —N[(C 1 -C 30 )alkyl] 2 , —NH[(C 0 -C 8 )alkylene-(C 3 -C 8 )cycloalkyl], —N[C 0 -C 8 )alkylene-(C 3 3 -C 8 )cycloalkyl] 2 , —NH[(CH 2 —CH 2 —O) 1-40 —(C 1 -C 4 )alkyl], —NH—(C 3 -C 8 )heterocyclyl, and —NH—(C 0 -C 8 )alkylene-aryl,
wherein aryl is selected from phenyl or naphthyl,
the (C 3 -C 8 )-heterocyclyl contains 1 N-atom and optionally two additional heteroatoms selected from O, N, and S, and
alkyl or cycloalkyl is unsubstituted or up to 5-fold substituted by —OH or a halogen selected from F, CI, Br, and I.

2. The compound, salt, or solvate according to claim 1 , wherein
X14 is an amino acid residue selected from Lys, Orn, Dab, and Dap, wherein the —NH 2 side chain group is functionalized by —C(O)—R 5 , and
X40 is an amino acid residue selected from Lys, Orn, Dab, and Dap, wherein the —NH 2 side chain group is optionally functionalized by —C(O)—R 5 ,
where R 5 is a lipophilic moiety selected from an acyclic (C 4 -C 30 ) hydrocarbon group which is linear, branched, saturated, or unsaturated, or a cyclic hydrocarbon group which is saturated, unsaturated, or aromatic, wherein the lipophilic moiety is optionally attached to the —NH 2 side chain group by a linker selected from the group consisting of (β-Ala) 1-4 , (γ-Glu) 1-4 , (ε-Ahx) 1-4 , and (GABA) 1-4 in all stereoisomeric forms.

3. The compound, salt, or solvate according to claim 1 , wherein
X14 is an amino acid residue selected from Lys, Orn, Dab, and Dap, wherein the —NH 2 side chain group is functionalized by —C(O)—R 5 ,
X40 is an amino acid residue selected from Lys, Orn, Dab, and Dap, wherein the —NH 2 side chain group is optionally functionalized by —C(O)—R 5 , and —C(O)—R 5 is selected from the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-,4-Hexadecanoylamino-butyryl-, 4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8, 12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, 4-octadecanoylamino-butyryl-, 4-((Z)-octadec-9-enoylamino)-butyryl-, 6-[(4,4-Diphenyl-cyclohexyloxy)-hydroxy-phosphoryloxy]-hexanoyl-, Hexadecanoyl-, (S)-4-Carboxy-4-(15-carboxy-pentadecanoylamino)-butyryl-, (S)-4-Carboxy-4-{3-[3-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-propionylamino]-propionylamino}-butyryl, (S)-4-Carboxy-4-{3-[(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyl-tridecyl)-chroman-6-yloxycarbonyl]-propionylamino}-butyryl-, (S)-4-Carboxy-4-((9Z,12Z)-octadeca-9, 12-dienoylamino)-butyryl-, (S)-4-Carboxy-4-[6-((2S,3R,4S,5R)-5-carboxy-2,3,4, 5-tetrahydroxy-pentanoylamino)-hexanoylamino]-butyryl, (S)-4-Carboxy-4-((2S,3R,4S,5R)-5-carboxy-2,3,4,5-tetrahydroxy-pentanoylamino)-butyryl, (S)-4-Carboxy-4-tetradecanoylamino-butyryl-, (S)-4-(11-Benzyloxycarbonyl-undecanoylamino)-4-carboxy-butyryl, (S)-4-Carboxy-4-[11-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexylcarbamoyl)-undecanoylamino]-butyryl-, (S)-4-Carboxy-4-((Z)-octadec-9-enoylamino)-butyryl-, (S)-4-Carboxy-4-(4-dodecyloxy-benzoylamino)-butyryl-, (S)-4-Carboxy-4-henicosanoylamino-butyryl-, (S)-4-Carboxy-4-docosanoylamino-butyryl-, (S)-4-Carboxy-4-((Z)-nonadec-10-enoylamino)-butyryl-, (S)-4-Carboxy-4-(4-decyloxy-benzoylamino)-butyryl-, (S)-4-Carboxy-4-[(4′-octyloxy-biphenyl-4-carbonyl)-amino]-butyryl-, (S)-4-Carboxy-4-(12-phenyl-dodecanoylamino)-butyryl-, (S)-4-Carboxy-4-icosanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-octadecanoylamino-butyrylamino)-butyryl-, 3-(3-Octadecanoylamino-propionylamino)-propionyl-, 3-(3-Hexadecanoylamino-propionylamino)-propionyl-, 3-Hexadecanoylamino-propionyl-, (S)-4-Carboxy-4-[(R)-4-((3R,5S,7R,8R,9R,10S,12S,13R,14R,17R)-3,7,12-trihydroxy-8,10,13-trimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoylamino]-butyryl-, (S)-4-Carboxy-4-[(R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl)-pentanoylamino]-butyryl-, (S)-4-Carboxy-4-((9S,10R)-9,10,16-trihydroxy-hexadecanoylamino)-butyryl-, Tetradecanoyl-, 11-Carboxy-undecanoyl-, 11-Benzyloxycarbonyl-undecanoyl, (S)-4-Carboxy-4-((S)-4-carboxy-4-tetradecanoylamino-butyrylamino)-butyryl-, 6-[Hydroxy-(naphthalen-2-yloxy)-phosphoryloxy]-hexanoyl-, 6-[Hydroxy-(5-phenyl-pentyloxy)-phosphoryloxy]-hexanoyl-, 4-(Naphthalene-2-sulfonylamino)-4-oxo-butyryl-, 4-(Biphenyl-4-sulfonylamino)-4-oxo-butyryl-, (S)-4-Carboxy-4-{(S)-4-carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy }-ethoxy)-acetylamino]-butyrylamino}-butyryl-, (S)-4-Carboxy-4-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyryl, (S)-4-Carboxy-2-{(S)-4-carboxy-2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy }-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetylamino]-butyrylamino}-butyryl, (S)-4-Carboxy-2-[2-(2-

Assignees

• Sanofi Sa

Inventors

• Haack Torsten
• Wagner Michael
• Henkel Bernd
• Stengelin Siegfried
• Evers Andreas
• Bossart Martin

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title