Cyclic peptide tyrosine tyrosine compounds as modulators of neuropeptide Y receptors

Patent metadata

Field	Value
Publication number	US-10968264-B2
Application number	US-201715794231-A
Country	US
Kind code	B2
Filing date	Oct 26, 2017
Priority date	Oct 27, 2016
Publication date	Apr 6, 2021
Grant date	Apr 6, 2021

Abstract

The present invention comprises compounds of Formula I.

wherein:
Z 4 , Z 7 , Z 9 , Z 11 , Z 22 , Z 23 , Z 26 , Z 30 , Z 34 , Z 35 , p, m, n, q, and BRIDGE are defined in the specification. The invention also relates to pharmaceutical compositions and methods for use thereof. The novel compounds are useful for preventing, treating or ameliorating diseases and disorders, such as obesity, type 2 diabetes, the metabolic syndrome, insulin resistance, and dyslipidemia, among others.

First claim

We claim:

1. A compound of Formula I:

wherein
p is 0 or 1;
m is 0, 1, 2, 3, 4, or 5;
n is 1, 2, 3, or 4;
q is 0 or 1; provided that q is 1 only when Z 30 is absent;
BRIDGE is -Ph-CH 2 —S—, -triazolyl-, —NHC(O)CH 2 S—, —SCH 2 C(O)NH—, —(OCH 2 CH 2 ) 2 NHC(O)CH 2 S, —NHC(O)—, or —CH 2 S—;
Z 4 is K, A, E, S, or R;
Z 7 is A or K;
Z 9 is G or K;
Z 11 is D or K;
Z 22 is A or K;
Z 23 is S or K;
Z 26 is A or H;
Z 30 is L, W, absent, or K;
provided that Z 30 is absent only when q is 1;
Z 34 is

Z 35 is

or a derivative thereof; wherein the derivative is the compound of Formula I that is modified by one or more processes comprising amidation, glycosylation, carbamylation, sulfation, phosphorylation, cyclization, lipidation, or pegylation; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound is a compound of Formula I or a compound of Formula I that is modified by one or more processes comprising amidation, lipidation, or pegylation; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein
BRIDGE is -Ph-CH 2 —S—, -triazolyl-, —NHC(O)CH 2 S—, —SCH 2 C(O)NH—, —(OCH 2 CH 2 ) 2 NHC(O)CH 2 S, —NHC(O)—, or —CH 2 S—;
Z 7 is A or K, wherein the amino side chain of said K is substituted with

wherein i is an integer of 0 to 24, and X═Br, I or Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl;
Z 9 is G or K, wherein the amino side chain of said K is substituted with

wherein t is 0, 1, or 2;
u is 0 or 1; and
v is 14, 16, or 18;

wherein i is an integer of 0 to 24, and X═Br, I or Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl;
Z 11 is D or K, wherein the amino side chain of said K is substituted with

wherein w is 0, 1, 2, or 4;
x is 0 or 1; and
y is 14, 16, or 18;

wherein i is an integer of 0 to 24, and X═Br, I or Cl,

or —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl;
Z 22 is A or K, wherein the amino side chain of said K is substituted with

wherein i is an integer of 0 to 24, and X═Br, I or Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl;
Z 23 is S or K, wherein the amino side chain of said K is substituted with

wherein i is an integer of 0 to 24, and X═Br, I or Cl, —C(O)CH 2 Br, —C(O)CH 2 I, or —C(O)CH 2 Cl;
Z 30 is L, W, absent, or K, provided that Z 30 is absent only when q is 1, wherein the amino side chain of said K is substituted with

wherein r is 0, 1, or 2;
s is 0 or 1; and
q 1 is 14, 16, or 18;

or a pharmaceutically acceptable salt thereof.

4. A compound of claim 3 , wherein
m is 0, 1, 2, 3, or 5;
n is 1, 2, or 4;
Z 7 is A or K, wherein the amino side chain of said K is substituted with

Z 9 is G or K, wherein the amino side chain of said K is substituted with

wherein t is 0;
u is 1; and
v is 14;

Z 11 is D or K, wherein the amino side chain of said K is substituted with

wherein w is 0, or 4;
x is 1; and
y is 14;

Z 22 is A or K, wherein the amino side chain of said K is substituted with

Z 23 is S or K, wherein the amino side chain of said K is substituted with

Z 30 is L, W, absent, or K, provided that Z 30 is absent only when q is 1, wherein the amino side chain of said K is substituted with

wherein r is 0, 1, or 2;
s is 0 or 1; and
q 1 is 14, 16, or 18;

or a pharmaceutically acceptable salt thereof.

5. A compound of claim 1 selected from the group consisting of SEQ ID NO: 1, SEQ ID NO:74, SEQ ID NO: 102, SEQ ID NO: 101, SEQ ID NO: 106, SEQ ID NO: 105, SEQ ID NO: 98, SEQ ID NO: 89, SEQ ID NO: 104, SEQ ID NO: 103, SEQ ID NO: 95, SEQ ID NO: 108, SEQ ID NO: 107, SEQ ID NO: 99, SEQ ID NO: 90, SEQ ID NO: 109, SEQ ID NO: 100, SEQ ID NO: 94, and SEQ ID NO:110, or a pharmaceutically acceptable salt thereof.

6. A conjugate comprising the compound of claim 1 and a half-life extension moiety conjugated thereto.

7. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier.

8. A method for treating or ameliorating obesity, comprising administering to a subject in need thereof an effective amount of the compound of claim 1 , or a form, composition or medicament thereof.

9. A method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is selected from the group consisting of obesity, type 2 diabetes, metabolic syndrome, insulin resistance and dyslipidemia comprising administering to a subject in need thereof an effective amount of the compound of claim 1 , or a form, composition or medicament thereof.

10. The method of claim 9 , wherein said syndrome, disorder or disease is type 2 diabetes.

11. A method of reducing food intake comprising administering to a subject in need thereof an effective amount of the compound of claim 1 , or a form, composition or medicament thereof.

12. A method of modulating Y2 receptor activity comprising administering to a subject in need thereof an

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Macielag Mark
• Patch Raymond J
• Zhang Rui
• Case Martin A
• Zhang Yue-Mei
• Wall Mark

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/08

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

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title