US2020155555A1PendingUtilityA1
Vitamin receptor drug delivery conjugates for treating inflammation
Est. expiryJun 25, 2027(~0.9 yrs left)· nominal 20-yr term from priority
Inventors:Christopher Paul LeamonIontcho Radoslavov VlahovYingjuan June LuKevin Yu WangFei YouPaul Joseph KleindlHari Krishna R. Santhapuram
A61K 31/436A61K 47/551A61K 47/545A61K 31/519A61P 9/10C07K 7/06
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Claims
Abstract
Described herein are compositions, methods, compounds, conjugates, and kits for use in targeted drug delivery using drug delivery conjugates containing hydrophilic spacer linkers for use in treating disease states caused by pathogenic cell populations, such as inflammatory cells.
Claims
exact text as granted — not AI-modified1 .- 2 . (canceled)
3 . A process for preparing a conjugate of the formula
B-L-A comprising
coupling a compound of the formula
wherein
AA is an amino acid;
R 1 is cysteine side chain, β-methyl cysteine side chain, or β,β-dimethyl cysteine side chain;
n is an integer from 0 to 100; and
-(AA) n - comprises at least one fragment of the formula
wherein
R is selected from the group consisting of H, alkyl, cycloalkyl, and arylalkyl; m is an integer from 1 to about 3; n1 is an integer from 1 to about 6; p is an integer from 1 to about 5; and (*) indicates the point of attachment to the rest of the compound,
with a compound of the formula
wherein A is an anti-inflammatory agent, in the presence of a base.
4 . The process of claim 3 , wherein the base is NaHCO 3 or DIPEA.
5 . The process of claim 3 or 4 , wherein the step of coupling is carried out in the presence of DMSO.
6 . The process of any one of claims 3 to 5 , wherein the step of coupling is carried out in the presence of a buffer.
7 . The process of claim 6 , wherein the buffer is a phosphate buffer.
8 . The process of any one of claims 3 to 7 , wherein the compound of the formula
is of the formula
9 . The process of any one of claims 3 to 7 , wherein the compound of the formula
is of the formula
10 . The process of any one of claims 3 to 9 , wherein n is from 3 to 7.
11 . The process of any one of claims 3 to 10 , wherein the compound of the formula
is of the formula
12 . The process of any one of claims 3 to 10 , further comprising
(a) contacting H-cysteine-(4-methoxytrityl)-2-chlorotrityl-resin in the presence of DIPEA and PyBOP with a compound of the formula
(b) contacting the product of step (a) with Fmoc-Glu(OtBu)-OH;
(c) contacting the product of step (b) with a compound of the formula
(d) contacting the product of step (c) with Fmoc-Glu-OtBu;
(e) contacting the product of step (d) with N 10 TFA-Pteroic Acid;
(f) contacting the product of step (e) with 2% hydrazine in DMF; and
(g) contacting the product of step (f) with a mixture of TFA, H 2 O, triisopropylsilane, and ethanedithiol.
13 . The process of any one of claims 3 to 10 , further comprising
(a) contacting H-cysteine-(4-methoxytrityl)-2-chlorotrityl-resin in the presence of DIPEA and PyBOP with a compound of the formula
(b) contacting the product of step (a) with Fmoc-Glu(OtBu)-OH;
(c) contacting the product of step (b) with a compound of the formula
(d) contacting the product of step (c) with Fmoc-Glu(OtBu)-OH;
(e) contacting the product of step (d) with a compound of the formula
(f) contacting the product of step (e) with Fmoc-Glu-OtBu;
(g) contacting the product of step (f) with N 10 TFA-Pteroic Acid;
(h) contacting the product of step (g) with 2% hydrazine in DMF; and
(i) contacting the product of step (h) with a mixture of TFA, H 2 O, triisopropylsilane, and ethanedithiol.
14 . The process of any one of claims 3 to 10 , further comprising
(a) contacting H-cysteine-(4-methoxytrityl)-2-chlorotrityl-resin in the presence of DIPEA and PyBOP with a compound of the formula
(b) contacting the product of step (a) with Fmoc-Glu(OtBu)-OH;
(c) contacting the product of step (b) with a compound of the formula
(d) contacting the product of step (c) with a compound of the formula
(e) contacting the product of step (d) with Fmoc-Glu(OtBu)-OH;
(f) contacting the product of step (e) with a compound of the formula
(g) contacting the product of step (f) with Fmoc-Glu-OtBu;
(h) contacting the product of step (g) with N 10 TFA-Pteroic Acid;
(i) contacting the product of step (i) with 2% hydrazine in DMF; and
(j) contacting the product of step (i) with a mixture of TFA, H 2 O, triisopropylsilane, and ethanedithiol.
15 . The process of any one of claims 3 to 10 , further comprising
(a) contacting H-cysteine-(4-methoxytrityl)-2-chlorotrityl-resin in the presence of DIPEA and PyBOP with a compound of the formula
(b) contacting the product of step (a) with Fmoc-Glu(OtBu)-OH;
(c) contacting the product of step (b) with a compound of the formula
(d) contacting the product of step (c) with Fmoc-Arg(Pbf)-OH;
(e) contacting the product of step (d) with a compound of the formula
(f) contacting the product of step (e) with Fmoc-Glu(OtBu)-OH;
(g) contacting the product of step (f) with a compound of the formula
(h) contacting the product of step (g) with Fmoc-Glu-OtBu;
(i) contacting the product of step (h) with N 10 TFA-Pteroic Acid;
(j) contacting the product of step (i) with 2% hydrazine in DMF; and
(k) contacting the product of step (j) with a mixture of TFA, H 2 O, triisopropylsilane, and ethanedithiol.
16 . A compound of the formula
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