IP Library › Granted Patent US 10,407,468

Granted Patent B2

US 10,407,468 · App. 15/467,810 · Granted Sep 10, 2019

Methods for synthesizing α4β7 peptide antagonists

Inventors: Ashok Bhandari (Pleasanton, CA); Suresh Kumar Manthati (Sunnyvale, CA); Mukund M. Mehrotra (San Jose, CA); Sampath-Kumar Anandan (Fremont, CA); Dinesh V. Patel (Fremont, CA)

Assignee: Protagonist Therapeutics, Inc.

C07K7/64 C07K1/006 C07K1/026 C07K1/061 C07K1/10 C07K1/1133 C07K1/1136 C07K1/20 C07K5/126 C07K7/02 C07K7/06 C07K14/705 C07K14/70546 A61K38/00

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Quick Facts

Patent No.: US 10,407,468
App. No.: 15/467,810
Granted: Sep 10, 2019
Kind: B2

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Abstract

The present invention provides methods of making α4β7 peptide monomer and dimer antagonists. Methods of the present invention include solid phase and solution phase methods, as well as synthesis via condensation of smaller peptide fragments. Methods of the present invention further include methods directed to the synthesis of peptides comprising one or more penicillamine residues.

Claims (436)

1. A protected peptide selected from the group consisting of:

(SEQ ID NO: 25)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr(tBu)-Leu-Pen(Trt)-Phe(4-tBu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-OH;

(SEQ ID NO: 25)

Fmoc-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr(tBu)-Leu-Pen(Trt)-Phe(4-tBu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-OH;

(SEQ ID NO: 87)

HN(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-Thr(tBu)-Leu-

Pen(Trt)-Phe(4-tBu)-β-homoGlu(O t Bu)-

D-Lys(Boc)-OH;

(SEQ ID NO: 25)

Fmoc-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr(tBu)-Leu-Pen(Acm)-Phe(4-tBu)-β-

homoGlu(OtBu)-D-Lys(Boc)-OH;

(SEQ ID NO: 87)

HN(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-Thr(tBu)-Leu-

Pen(Acm)-Phe(4-tBu)-β-homoGlu(OtBu)-

D-Lys(Boc)-OH;

(SEQ ID NO: 80)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Trt)-Phe(4- t Bu)-OH;

(SEQ ID NO: 80)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Acm)-Phe(4- t Bu)-OH;

(SEQ ID NO: 80)

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Acm)-Phe(4- t Bu)-OH;

(SEQ ID NO: 80)

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Trt)-Phe(4- t Bu)-OH;

(SEQ ID NO: 81)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Trt)-OH;

(SEQ ID NO: 81)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Acm)-OH;

(SEQ ID NO: 81)

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Acm)-OH;

(SEQ ID NO: 81)

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Trt)-OH;

(SEQ ID NO: 3)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-OH;

(SEQ ID NO: 3)

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-OH;

(SEQ ID NO: 73)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-OH;

(SEQ ID NO: 73)

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-OH;

(SEQ ID NO: 71)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-OH;

(SEQ ID NO: 71)

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-OH;

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-OH;

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-OH;

Ac-Pen(Trt)-N(Me)Arg(pbf)-OH;

Ac-Pen(Acm)-N(Me)Arg(pbf)-OH;

Phe(4- t Bu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 4)

H-Pen(Trt)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-

Lys(Boc)-NH 2 ;

(SEQ ID NO: 4)

H-Pen(Acm)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-

Lys(Boc)-NH 2 ;

(SEQ ID NO: 83)

Leu-Pen(Trt)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-

Lys(Boc)-NH 2 ;

(SEQ ID NO: 83)

Leu-Pen(Acm)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-

Lys(Boc)-NH 2 ;

(SEQ ID NO: 84)

Thr( t Bu)-Leu-Pen(Trt)-Phe(4- t Bu)-β-homoGlu(O t Bu)-

D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 84)

Thr( t Bu)-Leu-Pen(Acm)-Phe(4- t Bu)-β-homoGlu(O t Bu)-

D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 85)

Asp(O t Bu)-Thr( t Bu)-Leu-Pen(Trt)-Phe(4- t Bu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 85)

Asp(O t Bu)-Thr( t Bu)-Leu-Pen(Acm)-Phe(4- t Bu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 86)

Ser(tBu)-Asp(O t Bu)-Thr( t Bu)-Leu-Pen(Trt)-

Phe(4- t Bu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 86)

Ser(tBu)-Asp(O t Bu)-Thr( t Bu)-Leu-Pen(Acm)-

Phe(4- t Bu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 25)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr(tBu)-Leu-Pen(Trt)-Phe(4-tBu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 25)

Fmoc-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr(tBu)-Leu-Pen(Trt)-Phe(4-tBu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 87)

HN(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-Thr(tBu)-Leu-

Pen(Trt)-Phe(4-tBu)-β-homoGlu(OtBu)-

D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 25)

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr(tBu)-Leu-Pen(Acm)-Phe(4-tBu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 25)

Fmoc-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr(tBu)-Leu-Pen(Acm)-Phe(4-tBu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 87)

HN(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-Thr(tBu)-Leu-

Pen(Acm)-Phe(4-tBu)-β-homoGlu(O t Bu)-

D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 25)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr( ψMe,Me Pro)-Leu-Pen( ψMe,Me Pro)-

Phe(4-tBu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 25)

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr( ψMe,Me Pro)-Leu-Pen(Acm)-Phe(4-tBu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 25)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr( ψMe,Me Pro)-Leu-Pen(Trt)-Phe(4-tBu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 80)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen( ψMe,Me Pro)-Phe(4- t Bu)-OH;

(SEQ ID NO: 80)

Ac-Pen(Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen( ψMe,Me Pro)-Phe(4- t Bu)-OH;

(SEQ ID NO: 80)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Pro)-Phe(4- t Bu)-OH;

(SEQ ID NO: 80)

Ac-Pen(Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Pro)-Phe(4- t Bu)-OH;

(SEQ ID NO: 81)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen( ψMe,Me Pro)-OH;

(SEQ ID NO: 81)

Ac-Pen(Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen( ψMe,Me Pro)-OH;

(SEQ ID NO: 81)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Pro)-OH;

(SEQ ID NO: 81)

Ac-Pen(Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Pro)-OH;

(SEQ ID NO: 75)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-OH;

(SEQ ID NO: 75)

Ac-Pen(Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-OH;

(SEQ ID NO: 73)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-OH;

(SEQ ID NO: 73)

Ac-Pen(Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-OH;

(SEQ ID NO: 71)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-OH;

(SEQ ID NO: 71)

Ac-Pen(Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-OH;

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-OH;

Ac-Pen(Pro)-N(Me)Arg(pbf)-Ser(tBu)-OH;

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-OH;

Ac-Pen(Pro)-N(Me)Arg(pbf)-OH;

(SEQ ID NO: 86)

Ser(tBu)-Asp(O t Bu)-Thr( t Bu)-Leu-Pen( ψMe,Me Pro)-

Phe(4- t Bu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 86)

Ser( t Bu)-Asp(O t Bu)-Thr(Bu)-Leu-Pen(Pro)-Phe(4- t Bu)-

β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 85

Asp(O t Bu)-Thr( t Bu)-Leu-Pen( ψMe,Me Pro)-Phe(4- t Bu)-

β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 85)

Asp(O t Bu)-Thr( t Bu)-Leu-Pen(Pro)-Phe(4- t Bu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 84)

Thr( t Bu)-Leu-Pen( ψMe,Me Pro)-Phe(4- t Bu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 84)

Thr( t Bu)-Leu-Pen(Pro)-Phe(4- t Bu)-β-homoGlu(O t Bu)-

D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 83)

Leu-Pen( ψMe,Me Pro)-Phe(4- t Bu)-β-homoGlu(O t Bu)-

D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 83)

Leu-Pen(Pro)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-

Lys(Boc)-NH 2 ;

(SEQ ID NO: 4)

H-Pen( ψMe,Me Pro)-Phe(4- t Bu)-β-homoGlu(O t Bu)-

D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 4)

H-Pen(Pro)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-

Lys(Boc)-NH 2 ;

Phe(4- t Bu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 3)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser( t Bu)-

AspP(O t Bu)-Thr( t Bu)-Leu-OH;

and

(SEQ ID NO: 25)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser( t Bu)-

Asp(O t Bu)-Thr( t Bu)-Leu-Pen( ψMe,Me Pro)-Phe(4- t Bu)-

β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 .

2. The protected peptide according to claim 1 , wherein the peptide is Ac-Pen(Acm)-N(Me)Arg(pbf)-OH.

3. The protected peptide according to claim 1 , wherein the peptide is selected from the group consisting of:

(SEQ ID NO: 25)

Fmoc-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr(tBu)-Leu-Pen(Acm)-Phe(4-tBu)-β-

homoGlu(OtBu)-D-Lys(Boc)-OH;

(SEQ ID NO: 80)

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Acm)-Phe(4- t Bu)-OH;

(SEQ ID NO: 81)

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Acm)-OH;

(SEQ ID NO: 3)

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-OH;

(SEQ ID NO: 73)

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-OH;

(SEQ ID NO: 71)

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-OH;

and

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-OH.

4. The protected peptide according to claim 1 , wherein the peptide is β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 .

5. The protected peptide according to claim 1 , wherein the peptide is Ac-Pen(Trt)-N(Me)Arg(pbf)-OH.

6. The protected peptide according to claim 1 , wherein the peptide is selected from the group consisting of:

(SEQ ID NO: 25)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr(tBu)-Leu-Pen(Trt)-Phe(4-tBu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-OH;

(SEQ ID NO: 25)

Fmoc-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr(tBu)-Leu-Pen(Trt)-Phe(4-tBu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-OH;

(SEQ ID NO: 80)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Trt)-Phe(4- t Bu)-OH;

(SEQ ID NO: 80)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Acm)-Phe(4- t Bu)-OH;

(SEQ ID NO: 81)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Trt)-OH;

(SEQ ID NO: 81)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Acm)-OH;

(SEQ ID NO: 3)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-OH;

(SEQ ID NO: 73)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-OH;

(SEQ ID NO: 71)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-OH;

and

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-OH.

7. The protected peptide according to claim 1 , wherein the peptide is selected from the group consisting of:

(SEQ ID NO: 87)

HN(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-Thr(tBu)-Leu-

Pen(Trt)-Phe(4-tBu)-β-homoGlu(OtBu)-D-Lys(Boc)-OH;

and

(SEQ ID NO: 87)

HN(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-Thr(tBu)-Leu-

Pen(Acm)-Phe(4-tBu)-β-homoGlu(OtBu)-D-Lys(Boc)-OH.

8. The protected peptide according to claim 1 , wherein the peptide is selected from the group consisting of:

(SEQ ID NO: 4)

H-Pen(Acm)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-

Lys(Boc)-NH 2 ;

(SEQ ID NO: 83)

Leu-Pen(Acm)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-

Lys(Boc)-NH 2 ;

(SEQ ID NO: 25)

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr(tBu)-Leu-Pen(Acm)-Phe(4-tBu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

and

(SEQ ID NO: 25)

Fmoc-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr(tBu)-Leu-Pen(Acm)-Phe(4-tBu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 .

9. The protected peptide according to claim 1 , wherein the peptide is selected from the group consisting of:

(SEQ ID NO: 4)

H-Pen(Trt)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-

Lys(Boc)-NH 2 ;

(SEQ ID NO: 83)

Leu-Pen(Trt)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-

Lys(Boc)-NH 2 ;

(SEQ ID NO: 25)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr(tBu)-Leu-Pen(Trt)-Phe(4-tBu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 25)

Fmoc-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr(tBu)-Leu-Pen(Trt)-Phe(4-tBu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

and

(SEQ ID NO: 25)

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-

Thr( ψMe,Me Pro)-Leu-Pen(Trt)-Phe(4-tBu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 .

10. The protected peptide according to claim 1 , wherein the peptide is

Phe(4- t Bu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 84)

Thr( t Bu)-Leu-Pen(Acm)-Phe(4- t Bu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 85)

Asp(O t Bu)-Thr( t Bu)-Leu-Pen(Acm)-Phe(4- t Bu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 86)

Ser( t Bu)-Asp(O t Bu)-Thr( t Bu)-Leu-Pen(Acm)-Phe(4- t Bu)-

β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 .

11. The protected peptide according to claim 1 , wherein the peptide is selected from the group consisting of:

(SEQ ID NO: 87)

HN(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-Thr(tBu)-Leu-

Pen(Trt)-Phe(4-tBu)-β-homoGlu(OtBu)-D-Lys(Boc)-NH2;

and

(SEQ ID NO: 87)

HN(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-Thr(tBu)-Leu-

Pen(Acm)-Phe(4-tBu)-β-homoGlu(O t Bu)-

D-Lys(Boc)-NH 2 .

12. The protected peptide according to claim 1 , wherein the peptide is selected from the group consisting of:

(SEQ ID NO: 80)

Ac-Pen(Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Pro)-Phe(4- t Bu)-OH;

(SEQ ID NO: 81)

Ac-Pen(Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-Pen(Pro)-OH;

(SEQ ID NO: 75)

Ac-Pen(Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-Leu-OH;

(SEQ ID NO: 73)

Ac-Pen(Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-

Thr( t Bu)-OH;

(SEQ ID NO: 71)

Ac-Pen(Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-OH;

Ac-Pen(Pro)-N(Me)Arg(pbf)-Ser(tBu)-OH;

Ac-Pen(Pro)-N(Me)Arg(pbf)-OH;

(SEQ ID NO: 86)

Ser( t Bu)-Asp(O t Bu)-Thr( t Bu)-Leu-Pen(Pro)-

Phe(4- t Bu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 85)

Asp(O t Bu)-Thr( t Bu)-Leu-Pen(Pro)-Phe(4- t Bu)-

β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 84)

Thr( t Bu)-Leu-Pen(Pro)-Phe(4- t Bu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 83)

Leu-Pen(Pro)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-

Lys(Boc)-NH 2 ;

and

(SEQ ID NO: 4)

H-Pen(Pro)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-

Lys(Boc)-NH 2 .

13. The protected peptide according to claim 1 , wherein the peptide is selected from the group consisting of:

(SEQ ID NO: 25)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-

Asp(OtBu)-Thr( ψMe,Me Pro)-Leu-Pen( ψMe,Me Pro)-

Phe(4-tBu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 80)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-

Asp(O t Bu)-Thr( t Bu)-Leu-Pen( ψMe,Me Pro)-Phe(4- t Bu)-OH;

(SEQ ID NO: 80)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-

Asp(O t Bu)-Thr( t Bu)-Leu-Pen(Pro)-Phe(4- t Bu)-OH;

(SEQ ID NO: 81)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-

Asp(O t Bu)-Thr( t Bu)-Leu-Pen( ψMe,Me Pro)-OH;

(SEQ ID NO: 81)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-

Asp(O t Bu)-Thr( t Bu)-Leu-Pen(Pro)-OH;

(SEQ ID NO: 75)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-

Asp(O t Bu)-Thr( t Bu)-Leu-OH;

(SEQ ID NO: 73)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-

Asp(O t Bu)-Thr( t Bu)-OH;

(SEQ ID NO: 71)

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-

Asp(O t Bu)-OH;

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-Ser(tBu)-OH;

Ac-Pen( ψMe,Me Pro)-N(Me)Arg(pbf)-OH;

(SEQ ID NO: 85)

Asp(O t Bu)-Thr( t Bu)-Leu-Pen( ψMe,Me Pro)-

Phe(4- t Bu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 84)

Thr( t Bu)-Leu-Pen( ψMe,Me Pro)-Phe(4- t Bu)-β-

homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 83)

Leu-Pen( ψMe,Me Pro)-Phe(4- t Bu)-β-homoGlu(O t Bu)-

D-Lys(Boc)-NH 2 ;

(SEQ ID NO: 4)

H-Pen( ψMe,Me Pro)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-

Lys(Boc)-NH 2 ;

and

(SEQ ID NO: 86)

Ser(tBu)-Asp(O t Bu)-Thr( t Bu)-Leu-Pen( ψMe,Me Pro)-

Phe(4- t Bu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 .

14. The protected peptide according to claim 1 , wherein the peptide is

Phe(4- t Bu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 ;

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-Thr( t Bu)-Leu-Pen(Trt)-Phe(4- t Bu)-OH (SEQ ID NO:80); or

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-Thr( t Bu)-Leu-Pen(Trt)-OH (SEQ ID NO:81).

15. The protected peptide according to claim 1 , wherein the peptide is

Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-Thr( ψMe,Me Pro)-Leu-Pen(Acm)-Phe(4-tBu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 (SEQ ID NO:25).

16. The protected peptide according to claim 1 , wherein the peptide is

Thr( t Bu)-Leu-Pen(Trt)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 (SEQ ID NO:84);

Asp(O t Bu)-Thr( t Bu)-Leu-Pen(Trt)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 (SEQ ID NO:85); or

Ser(tBu)-Asp(O t Bu)-Thr( t Bu)-Leu-Pen(Trt)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 (SEQ ID NO:86).

17. The protected peptide according to claim 1 , wherein the peptide is

Ac-Pen(Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-Thr( t Bu)-Leu-Pen( ψMe,Me Pro)-Phe(4-tBu)-OH (SEQ ID NO:80); or

Ac-Pen(Pro)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-Thr( t Bu)-Leu-Pen( ψMe,Me Pro)-OH (SEQ ID NO:81).

18. The protected peptide according to claim 1 , wherein the peptide is Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-Thr( t Bu)-Leu-OH (SEQ ID NO:3).

19. The protected peptide according to claim 1 , wherein the peptide is Ac-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-Thr(tBu)-Leu-Pen(Acm)-Phe(4-tBu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 (SEQ ID NO:25).

20. The protected peptide according to claim 1 , wherein the peptide is H-Pen(Acm)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 (SEQ ID NO:4).

21. The protected peptide according to claim 1 , wherein the peptide is Fmoc-Pen(Acm)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-Thr(tBu)-Leu-Pen(Acm)-Phe(4-tBu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 (SEQ ID NO:25).

22. The protected peptide according to claim 1 , wherein the peptide is Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-Thr( t Bu)-Leu-OH (SEQ ID NO:3).

23. The protected peptide according to claim 1 , wherein the peptide is H-Pen(Trt)-Phe(4- t Bu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 (SEQ ID NO:4);

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(O t Bu)-Thr(tBu)-Leu-Pen(Trt)-Phe(4-tBu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 (SEQ ID NO:25);

Ac-Pen(Trt)-N(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-Thr( ψMe,Me Pro)-Leu-Pen(Trt)-Phe(4-tBu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 (SEQ ID NO:25); or

HN(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-Thr(tBu)-Leu-Pen(Trt)-Phe(4-tBu)-β-homoGlu(OtBu)-D-Lys(Boc)-NH 2 (SEQ ID NO:87).

24. The protected peptide according to claim 1 , wherein the peptide is HN(Me)Arg(pbf)-Ser(tBu)-Asp(OtBu)-Thr(tBu)-Leu-Pen(Acm)-Phe(4-tBu)-β-homoGlu(O t Bu)-D-Lys(Boc)-NH 2 (SEQ ID NO:87).

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 18, 2017

From: BHANDARI, ASHOK; MANTHATI, SURESH KUMAR; MEHROTRA, MUKUND M.; ANANDAN, SAMPATH-KUMAR; PATEL, DINESH V.

To: PROTAGONIST THERAPEUTICS, INC.

Reel/Frame 043897/0151 →

Continuity (4)

Provisional Application 62403527 · Oct 3, 2016

Provisional Application 62319045 · Apr 6, 2016

Provisional Application 62312345 · Mar 23, 2016

Related Publication 20170327541A1 · Nov 16, 2017

Cited By (4)

US 12,478,617 US 12,552,836 US 12,655,185 US 12,673,974