IP Library › Granted Patent US 9,745,344
Granted Patent B2
US 9,745,344 · App. 14/824,353 · Granted Aug 29, 2017

NPR-B agonists

Inventors: Frank Osterkamp (Berlin, DE); Heiko Hawlisch (Berlin, DE); Gerd Hummel (Berlin, DE); Tobias Knaute (Berlin, DE); Ulf Reimer (Berlin, DE); Ulrich Reineke (Berlin, DE); Bernadett Simon (Bonn, DE); Uwe Richter (Berlin, DE); Edgar Specker (Berlin, DE); Markus Woischnik (Berlin, DE); Mark R. Hellberg (Arlington, TX)
Assignee: Shire Orphan Therapies GmbH
C07K7/06C07K7/02C07K7/08
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Quick Facts
Patent No.
US 9,745,344
App. No.
14/824,353
Granted
Aug 29, 2017
Kind
B2
Abstract

Disclosed are novel compounds having NPR-B agonistic activity. Preferred compounds are linear peptides containing 8-13 conventional or non-conventional L- or D-amino acid residues connected to one another via peptide bonds.

Claims (106)

1. A compound selected from:

6054-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:228);

Occ-Sni-Mpa-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:244);

Occ-Sni-Ppa-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:245);

(6071-OH)-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:246);

5587-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:248);

(AR-201-48)-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:270);

(AR-201-48)-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:272);

(AR-201-58)-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:307);

(AR-201-59)-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:308);

Sbt-Sni-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:311);

Sbt-ala-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:313);

Nbt-ala-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:314);

(AR-201-72)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:339);

(AR-201-72)-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:340);

Miy-Gab-Hgl-ala-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:374);

Ac-Miy-Gab-Hgl-ala-Phe-arg-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:375);

Occ-Sni-Tyr-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:408);

Occ-Sni-Bmf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:409);

Occ-Sni-Phe-Ala-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:423);

Occ-Sni-Phe-nml-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:437);

2553-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:457);

6988-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:460);

1695-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:462);

Occ-Sni-Otf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:467);

Occ-Sni-NHfe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:474);

785-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:484);

3218-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:486);

1281-G-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:489);

1281-Bal-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:490);

Occ-Sni-Hfe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:504);

Occ-ala-Nmf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:505);

Gluc-Aoa-hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:533);

(1270)-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:535);

Occ-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:537);

(AR-314-170)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:555);

(AR-314-171)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:556);

(AR-385-008)-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:557); and

Occ-Sni-Phe-thr-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:565).

2. The compound of claim 1 selected from:

2553-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:457);

6988-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:460);

1695-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:462);

785-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:484);

3218-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:486);

1281-G-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:489);

1281-Bal-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:490);

Gluc-Aoa-hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:533);

(1270)-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:535); and

Occ-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:537).

3. A compound of the formula:

wherein

B is selected from the group consisting of R b1 — and R b2 —C(O)—, wherein:

R b1 is selected from the group consisting of C 6 -C 10 alkyl and C 6 -C 10 alkyl substituted by NR b4 R b5 ;

Rb2 is C 6 -C 10 alkyl substituted by NR b4 R b5 ; and

R b4 and R b5 are, independently, selected from the group consisting of H and C 1 -C 4 alkyl; and

R 11b is selected from the group consisting of H, C 1 -C 8 alkyl, C 4 -C 8 cycloalkyl, C 7 -C 12 bicycloalkyl, and C 1 -C 4 alkyl-C 4 -C 8 cycloalkyl.

4. The compound of claim 3 , wherein:

R 11b is selected from the group consisting of H and C 1 -C 8 alkyl.

5. A compound of the formula:

wherein

B is selected from the group consisting of R b1 — and R b2 —C(O)—, wherein:

R b1 is selected from the group consisting of C 6 -C 10 alkyl and C 6 -C 10 alkyl substituted by NR b4 R b5 ;

R b2 is C 6 -C 10 alkyl substituted by NR b4 R b5 ; and

R b4 and R b5 are, independently, selected from the group consisting of H and C 1 -C 4 alkyl; and

R 11b is selected from the group consisting of H, C 1 -C 8 alkyl, C 4 -C 8 cycloalkyl, C 7 -C 12 bicycloalkyl, and C 1 -C 4 alkyl-C 4 -C 8 cycloalkyl.

6. The compound of claim 5 , wherein:

R 11b is selected from the group consisting of H and C 1 -C 8 alkyl.

7. The compound of claim 1 , wherein said compound is selected from:

Occ-Sni-Mpa-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:244);

Occ-Sni-Ppa-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:245);

(AR-201-48)-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:272);

(AR-201-72)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:339);

Occ-Sni-Tyr-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:408);

Occ-Sni-Bmf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:409);

2553-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:457);

6988-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:460);

1695-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:462);

Occ-Sni-Otf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:467);

Occ-Sni-NHfe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:474);

785-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:484);

3218-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:486);

1281-G-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:489);

1281-Bal-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:490);

Occ-Sni-Hfe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:504);

Occ-ala-Nmf-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:505);

Gluc-Aoa-hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:533);

(1270)-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:535);

Occ-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:537);

(AR-314-170)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:555);

(AR-314-171)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:556); and

(AR-385-008)-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:557).

8. The compound of claim 7 , wherein said compound selected from:

(AR-201-72)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:339);

2553-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:457);

6988-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:460);

1695-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:462);

785-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:484);

3218-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:486);

1281-G-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:489);

1281-Bal-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:490);

Gluc-Aoa-hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:533);

(1270)-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:535);

Occ-Hgl-Sni-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:537);

(AR-314-170)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:555); and

(AR-314-171)-Phe-leu-Leu-Hyp-Nml-Asp-Arg-Ile-NH 2 (SEQ ID NO:556).

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 1, 2021
From: SHIRE ORPHAN THERAPIES GMBH
To: TAKEDA PHARMACEUTICAL COMPANY LIMITED
Reel/Frame 055105/0363 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 7, 2016
From: OSTERKAMP, FRANK; KNAUTE, TOBIAS; RICHTER, UWE; HAWLISCH, HEIKO; REIMER, ULF; SIMON, BERNADETT; HELLBERG, MARK R.; HUMMEL, GERD; REINEKE, ULRICH; SPECKER, EDGAR; WOISCHNIK, MARKUS
To: ALCON RESEARCH, LTD.
Reel/Frame 038215/0568 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 7, 2016
From: ALCON RESEARCH, LTD.
To: SHIRE ORPHAN THERAPIES GMBH
Reel/Frame 038215/0593 →
Continuity (4)
Division 14011855 · Aug 28, 2013
Division 12888556 · Sep 23, 2010
Provisional Application 61245960 · Sep 25, 2009
Related Publication 20160194357A1 · Jul 7, 2016