US2006194714A1PendingUtilityA1
Novel depsipeptides and process for preparing same
Est. expiryAug 6, 2021(expired)· nominal 20-yr term from priority
C07K 7/64A61K 38/15C07K 7/08Y02P20/55A61P 31/04C07K 11/02C07K 7/50
59
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Claims
Abstract
The present invention relates to novel depsipeptide compounds. The invention also relates to pharmaceutical compositions of these compounds and methods of using these compounds as antibacterial compounds. The invention also relates to methods of producing these novel depsipeptide compounds and intermediates used in producing these compounds.
Claims
exact text as granted — not AI-modified1 . A pharmaceutical composition comprising a compound of the Formula:
or a salt thereof; wherein:
(a) R is 2-butyl or isopropyl;
(b) each of R 1 and R 2 is independently methyl;
(c) R 3 is —CH 2 CH 2 CH 2 CH 2 R 9 ;
(d) R 4 is methoxy;
(e) R 5 is carboxyamino;
(f) R 6 is hydrido or methyl;
(g) each of R 7 and R 9 is independently amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino;
(h) provided that R 7 is other than
wherein each of R 11 and R 12 is hydrido, C 6 -C 18 unsubstituted alkanoyl, C 8 -C 18 unsubstituted alkenoyl, C 8 -C 18 unsubstituted alkyl, or C 8 -C 18 select substituted alkyl; or alternatively, R 11 and R 12 together are C 8 -C 18 alkylidenyl.
2 . The composition of claim 1 wherein R 7 is
wherein each of R aa , R aa2 and R aa3 is independently an amino acid side chain and wherein R 13 is amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino.
3 . A composition comprising a compound of the Formula
or a salt thereof; wherein:
(a) R is 2-butyl, isopropyl or 2-(2′-aminophenacyl);
(b) each of R 1 and R 6 is independently hydrido or methyl;
(c) R 4 is hydrido or methoxy;
(d) R 5 hydroxyl or carboxyamino;
(e) R 15 is hydrido,
wherein: R 18 is amino or hydroxyl; R 19 is hydrido or hydroxyl; and R 20 is carboxyamino or carboxymethyl;
(f) R 16 is methyl or —CH 2 CH 2 CH 2 R 21 ;
(g) R 17 is methyl or —CH 2 CH 2 CH 2 CH 2 R 22 ;
wherein each of R 21 and R 22 is independently amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino.
4 . The composition of claim 3 wherein each of R 21 and R 22 is independently —NHR 23 , wherein R 23 is an amino protecting group.
5 . The composition of claim 4 wherein the compound of Formula I is
wherein each of R 6 and R 14 is independently hydrido or methyl.
6 . A method of treating a bacterial infection in a subject, comprising administering to the subject a therapeutically-effective amount of a composition comprising a compound of the Formula:
or a salt thereof; wherein:
(a) R is 2-butyl, isopropyl or 2-(2′-aminophenacyl);
(b) each of R 1 and R 6 is independently hydrido or methyl;
(c) R 2 is methyl or —CH 2 CH 2 CH 2 R 8 ;
(d) R 3 is methyl or —CH 2 CH 2 CH 2 CH 2 R 9 ;
(e) R 4 is hydrido or methoxy;
(f) R 5 is hydroxyl or carboxyamino;
(g) each of R 7 , R 8 and R 9 is independently amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino;
(h) provided that
(1) when R 2 is —CH 2 CH 2 CH 2 R 8 , R 7 is other than
wherein R 10 is amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, iminoamino, or phosphonamino;
(2) when R 2 is methyl, R 7 is other than
wherein each of R 11 and R 12 is hydrido, C 6 -C 18 unsubstituted alkanoyl, C 8 -C 18 unsubstituted alkenoyl, C 8 -C 18 unsubstituted alkyl, or C 8 -C 18 select substituted alkyl; or alternatively, R 11 and R 12 together are C 8 -C 18 alkylidenyl.
7 . A process for preparing a compound of Formula I:
or a salt thereof; wherein:
(a) R is 2-butyl, isopropyl or 2-(2′-aminophenacyl);
(b) each of R 1 and R 6 is independently hydrido or methyl;
(c) R 2 is methyl or —CH 2 CH 2 CH 2 R 8 ;
(d) R 3 is methyl or —CH 2 CH 2 CH 2 CH 2 R 9 ;
(e) R 4 is hydrido or methoxy;
(f) R 5 is hydroxyl or carboxyamino;
(g) each of R 7 , R 8 and R 9 is independently amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino;
(h) provided that
(1) when R 2 is —CH 2 CH 2 CH 2 R 8 , R 7 is other than
wherein R 10 is amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, iminoamino, or phosphonamino;
(2) when R 2 is methyl, R 7 is other than
wherein each of R 11 and R 12 is hydrido, C 6 -C 18 unsubstituted alkanoyl, C 8 -C 18 unsubstituted alkenoyl, C 8 -C 18 unsubstituted alkyl, or C 8 -C 18 select substituted alkyl; or alternatively, R 11 and R 12 together are C 8 -C 18 alkylidenyl; comprising removing an amino protecting group from a compound of Formula XVII, or a salt thereof,
wherein R 28 is methyl or —CH 2 CH 2 CH 2 NHP; R 29 is methyl or —CH 2 CH 2 CH 2 CH 2 NHP; and P is an amino protecting group; provided that at least one of R 28 or R 29 is other than methyl.
8 . The process of claim 7 further comprising treating a compound of the Formula XVI,
or a salt thereof,
with a modifying agent to obtain the compound of Formula XVII, or a salt thereof.
9 . The process of claim 8 further comprising removing the terminal amino acid residue from a compound of Formula XV,
or a salt thereof,
wherein R 18 is amino or hydroxy; R 19 is hydrido or hydroxy;
to obtain the compound of Formula XVI, or a salt thereof.
10 . The process of claim 9 further comprising removing the terminal amino acid residue from a compound of Formula XIV
or a salt thereof,
wherein R 20 is carboxyamino or carboxymethyl;
to obtain the compound of Formula XV, or a salt thereof.
11 . The process of claim 10 further comprising removing the tryptophan amino acid residue from a compound of Formula XIII
or a salt thereof,
to obtain the compound of Formula XIV, or a salt thereof.
12 . The process of claim 11 further comprising deacylating a compound of Formula XII
or a salt thereof;
wherein R 25 is an alkyl group;
to obtain the compound of Formula XIII, or a salt thereof.
13 . The process of claim 12 further comprising protecting the free amine group(s) of a compound of Formula XI
or a salt thereof;
wherein R 26 methyl or —CH 2 CH 2 CH 2 NH 2 ; and R 27 is methyl or —CH 2 CH 2 CH 2 CH 2 NH 2 ;
to obtain the compound of Formula XII, or a salt thereof.
14 . A process for preparing a compound of Formula I:
or a salt thereof; wherein:
(a) R is 2-butyl, isopropyl or 2-(2′-aminophenacyl);
(b) each of R 1 and R 6 is independently hydrido or methyl;
(c) R 2 is methyl or —CH 2 CH 2 CH 2 R 8 ;
(d) R 3 is methyl or —CH 2 CH 2 CH 2 CH 2 R 9 ;
(e) R 4 is hydrido or methoxy;
(f) R 5 is hydroxyl or carboxyamino;
(g) each of R 7 , R 8 and R 9 is independently amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino;
(h) provided that
(1) when R 2 is —CH 2 CH 2 CH 2 R 8 , R 7 is other than
wherein R 10 is amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, iminoamino, or phosphonamino;
(2) when R 2 is methyl, R 7 is other than
wherein each of R 11 and R 12 is hydrido, C 6 -C 18 unsubstituted alkanoyl, C 8 -C 18 unsubstituted alkenoyl, C 8 -C 18 unsubstituted alkyl, or C 8 -C 18 select substituted alkyl; or alternatively, R 11 and R 12 together are C 8 -C 18 alkylidenyl;
comprising treating a compound of Formula Ia
or salt thereof,
wherein R 2a is methyl or —CH 2 CH 2 CH 2 NH 2 ; and R 3a is methyl or —CH 2 CH 2 CH 2 CH 2 NH 2 ; provided at least one of R 2a and R 3a is other than methyl; with a modifying agent.
15 . A process for preparing a compound of Formula I:
or a salt thereof; wherein:
(a) R is 2-butyl, isopropyl or 2-(2′-aminophenacyl);
(b) each of R 1 and R 6 is independently hydrido or methyl;
(c) R 2 is methyl or —CH 2 CH 2 CH 2 R 8 ;
(d) R 3 is methyl or —CH 2 CH 2 CH 2 CH 2 R 9 ;
(e) R 4 is hydrido or methoxy;
(f) R 5 is hydroxyl or carboxyamino;
(g) each of R 7 , R 8 and R 9 is independently amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino;
(h) provided that
(1) when R 2 is —CH 2 CH 2 CH 2 R 8 , R 7 is other than
wherein R 10 is amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, iminoamino, or phosphonamino;
(2) when R 2 is methyl, R 7 is other than
wherein each of R 11 and R 12 is hydrido, C 6 -C 18 unsubstituted alkanoyl, C 8 -C 18 unsubstituted alkenoyl, C 8 -C 18 unsubstituted alkyl, or C 8 -C 18 select substituted alkyl; or alternatively, R 11 and R 12 together are C 8 -C 18 alkylidenyl; comprising treating a compound of Formula XXVIII or a salt thereof;
wherein R 37 is methyl or —CH 2 CH 2 CH 2 R 8 ; and R 38 is methyl or —CH 2 CH 2 CH 2 CH 2 R 9 ; provided that at least one of R 37 and R 38 is other than methyl and further provided that each of R 8 and R 9 is other than amino;
with a modifying agent.
16 . The process of claim 15 further comprising removing the terminal amino acid residue from a compound of Formula XXVII
or a salt thereof;
wherein R 18 is amino or hydroxyl; and R 19 is hydrido or hydroxyl;
to obtain the compound of Formula XXVIII, or a salt thereof.
17 . The process of claim 16 further comprising removing the terminal amino acid residue from a compound of Formula XXVI
or a salt thereof;
wherein R 20 is carboxyamino or carboxymethyl;
to obtain the compound of Formula XXVII, or a salt thereof.
18 . The process of claim 17 further comprising removing the tryptophan amino acid residue from a compound of Formula XXV
or a salt thereof,
to obtain the compound of Formula XXVI, or a salt thereof.
19 . The process of claim 18 further comprising deacylating a compound of Formula XXIV
or a salt thereof;
wherein R 25 is an alkyl group;
to obtain the compound of Formula XXV, or a salt thereof.
20 . The process of claim 19 further comprising treating the free amine group(s) of a compound of Formula XI,
or a salt thereof;
wherein R 26 methyl or —CH 2 CH 2 CH 2 NH 2 ; and R 27 is methyl or —CH 2 CH 2 CH 2 CH 2 NR 2 ;
with a modifying agent to obtain the compound of Formula XXV, or a salt thereof.
21 . A process for preparing a compound of the Formula XXXII
or a salt thereof; wherein:
(a) R is 2-butyl, isopropyl or 2-(2′-aminophenacyl);
(b) each of R 1 and R 6 is independently hydrido or methyl;
(c) R 4 is hydrido or methoxy;
(d) R 5 is hydroxyl or carboxyamino;
(e) R 18 is amino or hydroxyl;
(f) R 19 is hydrido or hydroxyl;
(g) R 20 is carboxyamino or carboxymethyl;
(h) R 28 is methyl or —CH 2 CH 2 CH 2 NHP;
(i) R 29 is methyl or CH 2 CH 2 CH 2 CH 2 NHP;
(j) P is an amino protecting group;
(k) R 39 is independently amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino;
(l) provided that
(1) when R 2 is —CH 2 CH 2 CH 2 R 8 , R 7 is other than
wherein R 10 is amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, iminoamino, or phosphonamino;
(2) when R 2 is methyl, R 7 is other than
wherein each of R 11 and R 12 is hydrido, C 6 -C 18 unsubstituted alkanoyl, C 8 -C 18 unsubstituted alkenoyl, C 8 -C 18 unsubstituted alkyl, or C 8 -C 18 select substituted alkyl; or alternatively, R 11 and R 12 together are C 8 -C 18 alkylidenyl; comprising treating a compound of Formula XIV or a salt thereof, with a modifying agent.
22 . A process for preparing a compound of the Formula XXXIV
or a salt thereof; wherein:
(a) R is 2-butyl, isopropyl or 2-(2′-aminophenacyl);
(b) each of R 1 and R 6 is independently hydrido or methyl;
(c) R 4 is hydrido or methoxy;
(d) R 5 is hydroxyl or carboxyamino;
(e) R 18 is amino or hydroxyl;
(f) R 19 is hydrido or hydroxyl;
(g) R 28 is methyl or —CH 2 CH 2 CH 2 NHP;
(h) R 29 is methyl or —CH 2 CH 2 CH 2 CH 2 NHP;
(i) P is an amino protecting group;
(j) R 39 is independently amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino;
(k) provided that
(1) when R 2 is —CH 2 CH 2 CH 2 R 8 , R 7 is other than
wherein R 10 is amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, iminoamino, or phosphonamino;
(2) when R 2 is methyl, R 7 is other than
wherein each of R 11 and R 12 is hydrido, C 6 -C 18 unsubstituted alkanoyl, C 8 -C 18 unsubstituted alkenoyl, C 8 -C 18 unsubstituted alkyl, or C 8 -C 18 select substituted alkyl; or alternatively, R 11 and R 12 together are C 8 -C 18 alkylidenyl; comprising treating a compound of Formula XV or a salt thereof, with a modifying agent.
23 . The composition according to claim 1 wherein the compound is selected from:
R 7
R 9
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
NH 2
a) wherein R 14 is hydrido or methyl;
b) wherein R 7 ** is an amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino and
c) each of R aa4 , R aa5 , and R aa6 is independently an amino acid side chain.
24 . A composition comprising a compound of the Formula:
;
wherein R 6 is H or CH 3 and each of R 7 * and R 9 is independently amino, monosubstituted amino, disubstituted amino, acylamino, ureido, guanidino, carbamoyl, sulfonamino, thioacylamino, thioureido, iminoamino, or phosphonamino.
25 . A compound of the Formula 33:Join the waitlist — get patent alerts
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