US2016207957A1PendingUtilityA1
Amino diacids containing peptide modifiers
Assignee: CHEMICAL & BIOPHARMACEUTICAL LAB OF PATRAS S APriority: Aug 29, 2013Filed: Aug 28, 2014Published: Jul 21, 2016
Est. expiryAug 29, 2033(~7.1 yrs left)· nominal 20-yr term from priority
A61P 43/00C07K 14/605C07K 14/62C07K 1/04C07K 14/57509C07C 237/22A61K 38/00C07K 14/505C07K 14/575C07C 271/22C07K 1/1075C07C 271/16C07C 235/12C07C 269/04C07K 14/4703A61K 47/542C07C 233/47C07K 14/635C07K 14/695C07C 323/60A61K 47/62C07C 269/06C07K 1/107C07C 2603/18C07K 14/00C07K 14/473C07K 1/1077C07C 271/02C07C 323/52A61K 47/48038C07C 2103/18C08F 112/14Y02P20/55
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Claims
Abstract
The present invention relates to peptide modifier compounds of Formula (1), or a salt thereof, wherein: a is an integer from 1 to 10, more preferably from 1 to 3; b is an integer from 0 to 7; Z is a terminal group and Y is a bivalent group. Further aspects of the invention relate to intermediates in the preparation of compounds of Formula (1), and the use of compounds of Formula 1 in the synthesis of peptide derivatives.
Claims
exact text as granted — not AI-modified1 . A compound of Formula 1, or a salt thereof,
wherein:
a is an integer from 1 to 10, more preferably from 1 to 3;
b is an integer from 0 to 7;
Z is a terminal group selected from:
(a) a group of Formula 2
where * denotes the point of attachment to Y;
r is an integer from 1 to 12, more preferably from 2 to 6;
R 1 is NH 2 or OR 3 where R 3 is selected from H, alkyl, aryl and aralkyl;
R 2 is H or Pr, where Pr is an amino protecting group, preferably Fmoc;
(b) a group of Formula 4 or Formula 5,
where * denotes the point of attachment to Y; and
k and l are each independently an integer from 0 to 25;
(c) a group of Formula 6, 7, 8 or 37,
where * denotes the point of attachment to Y;
** indicates a bond to a group selected from OH, OR, NRR′ and Formula 9;
Pr is an amino protecting group;
k and l are each independently an integer from 0 to 25; and
R and R′ are each independently selected from H, alkyl and aralkyl;
(d) a group of Formula 10,
where * denotes the point of attachment to Y;
R 4 is the side chain of a natural or unnatural amino acid;
c is an integer from 1 to 12; and
** indicates a bond to a group selected from OH, OR, NRR′ and Formula 9; and
(e) a group of Formula 11 or Formula 12,
where * denotes the point of attachment to Y;
X is absent, or is selected from CH 2 , O, S and NR, where R is H, alkyl or aralkyl;
m, n, o, p are each independently an integer from 1 to 25; and
R 5 is H or Pr, where Pr is an amino protecting group, preferably selected from Fmoc, Boc and Trt;
each Y is independently a bivalent group selected from:
(a) a group of Formula 2′
where * denotes the point of attachment;
** indicates a bond to a group Z as defined above or another group Y;
r is an integer from 1 to 12, more preferably from 2 to 6; and
R 1 is NH 2 or OR 3 , where R 3 is selected from H, alkyl, aryl and aralkyl;
(b) a group of Formula 6′, 7′ or 8′,
where * denotes the point of attachment;
** indicates a bond to a group Z as defined above or another group Y;
k and l are each independently an integer from 1 to 25;
Pr is an amino protecting group; and
R is selected from H, alkyl and aralkyl;
(c) a group of Formula 10′,
where R 4 is the side chain of a natural or unnatural amino acid side chain;
c is an integer from 1 to 12;
* denotes the point of attachment; and
** indicates a bond to a group Z as defined above or another group Y; and
(d) a group of Formula 11′ or Formula 12′,
where * denotes the point of attachment;
** denotes a bond to a group Z as defined above or another group Y;
X is absent, or is selected from CH 2 , O, S and NR, where R is H, alkyl or aralkyl;
and m, n, o, p are each independently an integer from 1 to 25.
2 . A compound according to claim 1 which is of Formula 13
wherein Pr is a protecting group, and a, r and R are as defined in claim 1 .
3 . A compound according to claim 2 wherein Pr is selected from trityl, 2-chloro-trityl, 4-methyl-trityl and 4-methoxy-trityl, more preferably trityl.
4 . A compound according to claim 1 wherein R 1 is O-alkyl, more preferably, O t Bu.
5 . A compound according to claim 1 which is selected from the following:
6 . A compound of Formula 1 according to 1 which is of Formula 16
wherein Z, Y, a, b, r and R 1 are as defined in claim 1 .
7 . A resin conjugate of Formula 18
wherein:
R 1 is NH 2 or OR 3 , where R 3 is selected from H, alkyl, aryl and aralkyl
r is an integer from 1 to 12, more preferably from 2 to 6;
Resin is an acid sensitive resin which allow the cleavage of compounds from the resin selectively in the presence of groups of the t Bu-type;
b is an integer from 0 to 7;
Z is a terminal group selected from:
(a) a group of Formula 2
where * denotes the point of attachment to Y;
r is an integer from 1 to 12, more preferably from 2 to 6;
R 1 is NH 2 or OR 3 , where R 3 is selected from H, alkyl, aryl and aralkyl;
R 2 is H or Pr, where Pr is an amino protecting group, preferably Fmoc;
(b) a group of Formula 4 or Formula 5,
where * denotes the point of attachment to Y; and
k and l are each independently an integer from 0 to 25;
(c) a group of Formula 6, 7, 8 or 37,
where * denotes the point of attachment to Y;
** indicates a bond to a group selected from OH, OR, NRR′ and Formula 9;
Pr is an amino protecting group;
k and l are each independently an integer from 0 to 25; and
R and R′ are each independently selected from H, alkyl and aralkyl;
(d) a group of Formula 10,
where * denotes the point of attachment to Y;
R 4 is the side chain of a natural or unnatural amino acid;
c is an integer from 1 to 12; and
** indicates a bond to a group selected from OH, OR, NRR′ and Formula 9; and
(e) a group of Formula 11 or Formula 12,
where * denotes the point of attachment to Y;
X is absent, or is selected from CH 2 , O, S and NR, where R is H, alkyl or aralkyl;
m, n, o, p are each independently an integer from 1 to 25; and
R 5 is H or Pr, where Pr is an amino protecting group, preferably selected from Fmoc, Boc and Trt;
each Y is independently a bivalent group selected from:
(a) a group of Formula 2′
where * denotes the point of attachment;
** indicates a bond to a group Z as defined above or another group Y;
r is an integer from 1 to 12, more preferably from 2 to 6; and
R 1 is NH 2 or OR 3 , where R 3 is selected from H, alkyl, aryl and aralkyl;
(b) a group of Formula 6′, 7′ or 8′,
where * denotes the point of attachment;
** indicates a bond to a group Z as defined above or another group Y;
k and l are each independently an integer from 1 to 25;
Pr is an amino protecting group; and
R is selected from H; alkyl and aralkyl;
(c) a group of Formula 10′
where R 4 is the side chain of a natural or unnatural amino acid side chain;
c is an integer from 1 to 12;
* denotes the point of attachment; and
** indicates a bond to a group Z as defined above or another group Y; and
(d) a group of Formula 11′ or Formula 12′,
where * denotes the point of attachment;
** denotes a bond to a group Z as defined above or another group Y;
X is absent, or is selected from CH 2 , O, S and NR, where R is H, alkyl or aralkyl;
and m, n, o, p are each independently an integer from 1 to 25.
8 . A resin conjugate according to claim 7 where the acid sensitive resin is selected from trityl, 2-chloro-trityl, 4-methyl-trityl and 4-methoxy-trityl resin, more preferably 2-chlorotrityl resin.
9 . A resin conjugate of Formula 18 according to claim 7 which is selected from the following:
where P is a polymer matrix.
10 . A process for the preparation of a compound of Formula 13, said process comprising the steps of:
(i) coupling a protected diacid derivative of Formula 14 with an N α -protected diamino acid derivative of Formula 19; and) (ii) optionally hydrolysing the product formed in step (i) where R is other than H to form a compound of Formula 13.
11 . A process for the preparation of a compound of Formula 16, said process comprising the steps of:
(i) coupling a protected diacid derivative of Formula 15 with an N α -protected diamino acid derivative of Formula 19; and (ii) optionally hydrolysing the product formed in step (i) where R is other than H to form a compound of Formula 16.
12 . A process for preparing a compound of Formula 15, wherein r is an integer from 1 to 12, more preferably from 2 to 6, said process comprising the steps of:
(i) reacting a compound of Formula 24, where R 1 is NH 2 or OR 3 , where R 3 is selected from H, alkyl, aryl and aralkyl, with a resin to form a resin-bound compound of Formula 23; (ii) deprotecting said compound of Formula 23 to form a compound of Formula 17; (iii) converting said compound of Formula 17 into a compound of Formula 18 by reacting with a compound of formula Z—(Y) b —OH; and (iv) removing said compound of Formula 18 from the resin by treating with a mild acid to form a compound of Formula 15.
13 . A process for preparing a peptide derivative of Formula 22, said process comprising the steps of:
(i) reacting a resin-bound peptide of formula H-Aaa 1 -Aaa 2 - . . . Aaa n -Resin with a compound of Formula 1 to form a compound of Formula 20; (ii) removing the protecting group from the compound of Formula 20 and coupling with an at least N-terminally protected amino acid or peptide having a free or activated carboxylic acid function and optionally repeating this step to give a compound of Formula 21; (iii) removing said compound of Formula 21 from the resin to form a compound of Formula 22.
14 . A peptide derivative obtained by or obtainable by the process of claim 13 .
15 . A process for preparing a compound of Formula 1 as defined in claim 1 , said process comprising reacting a compound of Formula 19 with a compound of Formula Z—(Y) b —OH.
16 . A compound of formula:
Z—(Y) b —OH
wherein: b is an integer from 0 to 7; Z is a terminal group selected from: (a) a group of Formula 2
where * denotes the point of attachment to Y;
r is an integer from 1 to 12, more preferably from 2 to 6;
R 1 is NH 2 or OR 3 , where R 3 is selected from H, alkyl, aryl and aralkyl;
R 2 is H or Pr, where Pr is an amino protecting group, preferably Fmoc;
(b) a group of Formula 4 or Formula 5,
where * denotes the point of attachment to Y; and
k and l are each independently an integer from 0 to 25;
(c) a group of Formula 6, 7, 8 or 37
where * denotes the point of attachment to Y;
** indicates a bond to a group selected from OH, OR, NRR′ and Formula 9;
Pr is an amino protecting group;
k and l are each independently an integer from 0 to 25;
p is an integer from 1 to 20;
q is an integer from 5 to 20; and
R and R′ are each independently selected from H, alkyl and aralkyl;
(d) a group of Formula 10,
where * denotes the point of attachment to Y;
R 4 is the side chain of a natural or unnatural amino acid;
c is an integer from 1 to 12; and
** indicates a bond to a group selected from OH, OR, NRR′ and Formula 9; and
(e) a group of Formula 11 or Formula 12,
where * denotes the point of attachment to Y;
X is absent, or is selected from CH 2 , O, S and NR, where R is H, alkyl or aralkyl;
m, n, o, p are each independently an integer from 1 to 25; and
R 5 is H or Pr, where Pr is an amino protecting group, preferably selected from Fmoc, Boc and Trt;
each Y is independently a bivalent group selected from:
(a) a group of Formula 2′
where * denotes the point of attachment;
** indicates a bond to a group Z as defined above or another group Y;
r is an integer from 1 to 12, more preferably from 2 to 6; and
R 1 is NH 2 or OR 3 , where R 3 is selected from H, alkyl, aryl and aralkyl;
(b) a group of Formula 6′, 7′ or 8′,
where * denotes the point of attachment;
** indicates a bond to a group Z as defined above or another group Y;
k and l are each independently an integer from 1 to 25;
Pr is an amino protecting group; and
R is selected from H, alkyl and aralkyl;
(c) a group of Formula 10′,
where is the side chain of a natural or unnatural amino acid side chain;
c is an integer from 1 to 12;
* denotes the point of attachment; and
** indicates a bond to a group Z as defined above or another group Y; and
(d) a group of Formula 11′ or Formula 12′,
where * denotes the point of attachment;
** denotes a bond to a group Z as defined above or another group Y;
X is absent, or is selected from CH 2 , O, S and NR, where R is H, alkyl or aralkyl;
and m, n, o, p are each independently an integer from 1 to 25.
17 . A compound according to claim 16 which is selected from the following:
18 . (canceled)
19 . (canceled)
20 . (canceled)
21 . (canceled)
22 . A peptide, or a fragment thereof, wherein at least one amino acid residue in said peptide or fragment thereof is modified by side chain attachment of a peptide modifier derived from Z—(Y) b —OH, wherein Z, Y and b are as defined in claim 1 .
23 . A peptide of formula 38, or a fragment or variant thereof,
wherein:
a, b, Z and Y are as defined in claim 1 ;
Q 1 and Q 2 are each independently a terminal group; and
Aaa x Aaa y . . . Aaa z and Aaa 1 Aaa 2 . . . Aaa n are each independently a natural or synthetic peptide comprising 1 to 100 natural or unnatural amino acid residues, each of which is optionally protected.
24 . A peptide, or a fragment thereof, according to claim 22 which is selected from the following:
25 . (canceled)
26 . A pharmaceutical composition comprising a peptide, or a fragment thereof or a variant thereof, according to claim 22 admixed with a pharmaceutically acceptable excipient, diluent or carrier.
27 . (canceled)Join the waitlist — get patent alerts
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