Cyclic peptidomimetic compounds as immunomodulators

Patent metadata

Field	Value
Publication number	US-9233940-B2
Application number	US-201414478806-A
Country	US
Kind code	B2
Filing date	Sep 5, 2014
Priority date	Sep 6, 2013
Publication date	Jan 12, 2016
Grant date	Jan 12, 2016

Abstract

Compounds of Formula (I) are provided:

and pharmaceutically acceptable salts and stereoisomers thereof; wherein:

R 1 is a side chain of amino acid Ala, Ser, Thr or Leu;

R 2 is a side chain of amino acid Asp, Glu, Gln or Asn;

[Aaa] is an amino acid residue selected from Ser, ASP, Ala, Ile, Phe, Trp, Lys, Glu or Thr;

R 3 is hydrogen or alkyl;

each of R 4 and R 4 ′ independently are hydrogen or alkyl;

both R a and R a ′ are hydrogen; or together are an oxo (═O) group;

both R b and R b ′ are hydrogen; or together are an oxo (═O) group;

L is

X is CH 2 , O or S;

R 5 is hydrogen or alkyl;

m is an integer from 1 to 3; and

n is an integer from 2 to 20.

The compounds are useful for treatment of disorders via immunopotentiation comprising inhibition of immunosuppressive signal induced due to PD-1, PD-L1, or PD-L2 and therapies using them.

First claim

What is claimed is:

1. A compound of formula (I)

or a pharmaceutically acceptable salt or a stereoisomer thereof;
wherein,
R 1 is a side chain of amino acid Ala, Ser, Thr or Leu;
R 2 is a side chain of amino acid Asp, Glu, Gln or Asn;
[Aaa] is an amino acid residue selected from Ser, Asp, Ala, Ile, Phe, Trp, Lys, Glu or Thr;
R 3 is hydrogen or alkyl;
each of R 4 and R 4 ′ independently are hydrogen or alkyl;
both R a and R a ′ are hydrogen; or together are an oxo (═O) group;
both R b and R b ′ are hydrogen; or together are an oxo (═O) group;
L is

X is CH 2 , O or S;
R 5 is hydrogen or alkyl;

m is an integer from 1 to 3; and
n is an integer from 2 to 20.

2. The compound according to claim 1 , wherein the compound of formula (I) is a compound of formula (IA):

or a pharmaceutically acceptable salt or a stereoisomer thereof;
wherein,
R 1 is a side chain of amino acid Ala, Ser, Thr or Leu;
R 2 is a side chain of amino acid Asp, Glu, Gln or Asn;
[Aaa] is an amino acid residue selected from Ser, Asp, Ala, Ile, Phe, Trp, Lys, Glu or Thr;
R 3 is hydrogen or alkyl;
each of R 4 and R 4 ′ independently are hydrogen or alkyl;
both R a and R a ′ are hydrogen; or together are an oxo (═O) group; and
both R b and R b ′ are hydrogen; or together are an oxo (═O) group.

3. The compound according to claim 1 , wherein the compound of formula (I) is a compound of formula (IB):

or a pharmaceutically acceptable salt or a stereoisomer thereof;
wherein,
R 1 is a side chain of amino acid Ala, Ser, Thr or Leu;
R 2 is a side chain of amino acid Asp, Glu, Gln or Asn; and
[Aaa] is an amino acid residue selected from Ser, Asp, Ala, Ile, Phe, Trp, Lys, Glu or Thr.

4. The compound according to claim 1 , wherein the compound of formula (I) is a compound of formula (IC):

or a pharmaceutically acceptable salt or a stereoisomer thereof;
wherein,
R 1 is a side chain of amino acid Ala, Ser, Thr or Leu;
R 2 is a side chain of amino acid Asp, Glu, Gln or Asn; and
[Aaa] is an amino acid residue selected from Ser, Asp, Ala, Ile, Phe, Trp, Lys, Glu or Thr.

5. The compound according to claim 1 , wherein,
R 1 is a side chain of amino acid Ser or Thr;
R 2 is aside chain of amino acid Asp, Asn or Glu;
[Aaa] is an amino acid residue Ser or Thr;
R 3 , R 4 and R 4 ′ independently are hydrogen;
both R a and R a ′ together represent an oxo (═O) group;
both R b and R b ′ together represent an oxo (═O) group;
L is —C(O)—(CH 2 ) m —(X—CH 2 —CH 2 ) n —NH—;
X is CH 2 or O;
m is an integer from 1 to 3; and
n is an integer from 2 to 20;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

6. The compound according to claim 1 , wherein R 4 is C 1-5 alkyl; or R 4 ′ is C 1-5 alkyl.

7. A pharmaceutical composition comprising at least one compound according to claim 1 or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

8. The pharmaceutical composition according to claim 7 further comprising at least one of an anticancer agent, chemotherapy agent, or antiproliferative compound.

9. A compound having a structural formula selected from the group consisting of

Com-

pound

No.
Structure

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

Assignees

• Sasikumar Pottayil Govindan Nair
• Ramachandra Muralidhara
• Naremaddepalli Seetharamaiah Setty Sudarshan
• Aurigene Discovery Tech Ltd

Inventors

• Sasikumar Pottayil Govindan Nair
• Ramachandra Muralidhara
• Naremaddepalli Seetharamaiah Setty Sudarshan

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P31/20

  for DNA viruses · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title