IP Library › Granted Patent US 8,299,023
Granted Patent B2
US 8,299,023 · App. 12/547,076 · Granted Oct 30, 2012

Neuropeptide-2 receptor (Y-2R) agonists

Assignee: Hoffmann-La Roche Inc.
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Quick Facts
Patent No.
US 8,299,023
App. No.
12/547,076
Granted
Oct 30, 2012
Kind
B2
Abstract

Provided herein are neuropeptide-2 receptor agonists of the formula (I): Y—R 1 —R 2 —X—R 3 —R 4 —R 5 —R 6 —R 7 —R 8 —R 9 —R 10 —R 11 —R 12 —R 13 —R 14 —NH 2   (I) (SEQ ID NO: 1), as well as pharmaceutically acceptable salts, derivatives and fragments thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, obesity and diabetes.

Claims (39)

1. A neuropeptide-2 receptor agonist of the formula (I):

Y—R 1 —R 2 —X—R 3 —R 4 —R 5 —R 6 —R 7 —R 8 —R 9 —R 10 —R 11 —R 12 —R 13 —R 14 —NH 2   (I) (SEQ ID NO: 1),

wherein:

X is (4-Aminomethyl-biphenyl-3-yl)-acetic acid (Cba), (5-piperazin-1-yl-indole-1-yl)-acetic acid (Cip), 3-(4-oxo-6-piperazin-1-yl-4H-quinazolin-3-yl)-propionic acid (HomPqa), (6-[1,4]diazepan-1-yl-4-oxo-4H-quinazolin-3-yl)-acetic acid (Dqa), (6-Oxo-2-piperazin-1-yl-1,6-dihydropurin-7-yl)-acetic acid (Pdp), (2-Piperazin-1-yl-purin-7-yl)-acetic acid (Ppa), (6-Amino-2-piperazin-1-yl-9H-purin-8-yl)-acetic acid (Appa), ((1R,4S)-6-2-Aza-bicyclo[2.2.1]hept-5-yl-4-oxo-4H-quinazolin)-acetic acid (Bqa) or, (1-Oxo-7-piperazin-1-yl-1H-isoquinolin-2-yl)-acetic acid (Pipa),

Y is H or an acyl moiety,

R 1 is Ile, Ala, (D)Ile, N-methyl Ile, Aib, 1-1Aic, 2-2 Aic, Ach or Acp,

R 2 is Lys, Ala, (D)Lys, N-methyl lys, Nle or (Lys-Gly),

R 3 is Arg, Ala, (D)Arg, N-methyl Arg, Phe, 3,4,5-Trifluoro Phe or 2,3,4,5,6-Pentafluoro Phe,

R 4 is His, Ala, (D)His, N-methyl His, 4-MeOApc, 3-Pal or 4-Pal,

R 5 is Tyr, Ala, (D)Tyr, N-methyl Tyr, Trp, Tic, Bip, Dip, (1)Nal, (2)Nal, 3,4,5-TrifluoroPhe or 2,3,4,5,6-Pentafluoro Phe,

R 6 is Leu, Ala, (D)Leu or N-methyl Leu,

R 7 is Asn, Ala or (D)Asn,

R 8 is Leu or Trp,

R 9 is Val, Ala, (D)Val or N-methyl Val,

R 10 is Thr, Ala or N-methyl Thr,

R 11 is Arg, (D)Arg or N-methyl Arg,

R 12 is Gln or Ala,

R 13 is Arg, (D)Arg or N-methyl Arg, and

R 14 is Tyr, (D) Tyr or N-methyl Tyr, Phe, (1) Nal, (2) Nal, Cha, C-alpha-methyl Tyr, or Trp,

or a pharmaceutically acceptable salt thereof.

2. The neuropeptide-2 receptor agonist according to claim 1 , wherein:

X is (4-Aminomethyl-biphenyl-3-yl)-acetic acid (Cba), (5-piperazin-1-yl-indole-1-yl)-acetic acid (Cip), 3-(4-oxo-6-piperazin-1-yl-4H-quinazolin-3-yl)-propionic acid (HomPqa), (6-[1,4]diazepan-1-yl-4-oxo-4H-quinazolin-3-yl)-acetic acid (Dqa), (6-Oxo-2-piperazin-1-yl-1,6-dihydropurin-7-yl)-acetic acid (Pdp), (2-Piperazin-1-yl-purin-7-yl)-acetic acid (Ppa), (6-Amino-2-piperazin-1-yl-9H-purin-8-yl)-acetic acid (Appa), ((1R,4S)-6-2-Aza-bicyclo[2.2.1]hept-5-yl-4-oxo-4H-quinazolin)-acetic acid (Bqa) or, (1-Oxo-7-piperazin-1-yl-1H-isoquinolin-2-yl)-acetic acid (Pipa), and

Y is an acyl moiety (SEQ ID NO: 14).

3. The neuropeptide-2 receptor agonist according to claim 1 , having formula (II):

Y-Ile-Lys-X-Arg-His-Tyr-Leu-Asn-Trp-Val-Thr-Arg-Gln-(NMe)Arg-Tyr-NH 2   (II) (SEQ ID NO: 2)

wherein:

X is (4-Aminomethyl-biphenyl-3-yl)-acetic acid (Cba), (5-piperazin-1-yl-indole-1-yl)-acetic acid (Cip), 3-(4-oxo-6-piperazin-1-yl-4H-quinazolin-3-yl)-propionic acid (HomPqa), (6-[1,4]diazepan-1-yl-4-oxo-4H-quinazolin-3-yl)-acetic acid (Dqa), (6-Oxo-2-piperazin-1-yl-1,6-dihydropurin-7-yl)-acetic acid (Pdp), (2-Piperazin-1-yl-purin-7-yl)acetic acid (Ppa), (6-Amino-2-piperazin-1-yl-9H-purin-8-yl)-acetic acid (Appa), ((1R,4S)-6-2-Aza-bicyclo[2.2.1]hept-5-yl-4-oxo-4H-quinazolin)-acetic acid (Bqa) or, (1-Oxo-7-piperazin-1-yl-1H-isoquinolin-2-yl)-acetic acid (Pipa), and

Y is an acyl moiety.

4. The neuropeptide-2 receptor agonist according to claim 1 , selected from the group consisting of:

Ac-Ile-Lys-Cba-Arg-His-Tyr-Leu-Asn-Trp-Val-Thr-Arg-Gln-(NMe)Arg-Tyr-NH 2 (SEQ ID NO: 5),

Ac-Ile-Lys-Cip-Arg-His-Tyr-Leu-Asn-Trp-Val-Thr-Arg-Gln-(NMe)Arg-Tyr-NH 2 (SEQ ID NO: 6),

Ac-Ile-Lys-HomPqa-Arg-His-Tyr-Leu-Asn-Trp-Val-Thr-Arg-Gln-(NMe)Arg-Tyr-NH 2 (SEQ ID NO: 7 ,

Ac-Ile-Lys-Dqa-Arg-His-Tyr-Leu-Asn-Trp-Val-Thr-Arg-Gln-(NMe)Arg-Tyr-NH 2 (SEQ ID NO: 8),

Ac-Ile-Lys-Pdp-Arg-His-Tyr-Leu-Asn-Trp-Val-Thr-Arg-Gln-(NMe)Arg-Tyr-NH 2 (SEQ ID NO: 9),

Ac-Ile-Lys-Ppa-Arg-His-Tyr-Leu-Asn-Trp-Val-Thr-Arg-Gln-(NMe)Arg-Tyr-NH 2 (SEQ ID NO: 10),

Ac-Ile-Lys-Appa-Arg-His-Tyr-Leu-Asn-Trp-Val-Thr-Arg-Gln-(NMe)Arg-Tyr-NH 2 (SEQ ID NO: 11),

Ac-Ile-Lys-Bqa-Arg-His-Tyr-Leu-Asn-Trp-Val-Thr-Arg-Gln-(NMe)Arg-Tyr-NH 2 (SEQ ID NO: 12) and

Ac-Ile-Lys-Pipa-Arg-His-Tyr-Leu-Asn-Trp-Val-Thr-Arg-Gln-(NMe)Arg-Tyr-NH 2 (SEQ ID NO: 13).

5. A pharmaceutical composition, comprising a therapeutically effective amount of the neuropeptide-2 receptor agonist according to claim 1 , or a salt thereof, and a pharmaceutically acceptable carrier.

Continuity (2)
Provisional Application 61097621 · Sep 17, 2008
Related Publication 20100069307A1 · Mar 18, 2010