US2012258043A1PendingUtilityA1
Linkable Lewis X Analogs
Est. expiryNov 29, 2020(expired)· nominal 20-yr term from priority
Inventors:Ramachandran RanganathanKondareddiar RamalingamRadhakrishna K. PillaiEdmund R. MarinelliRolf E. Swenson
A61P 3/10A61P 7/02A61P 43/00A61P 9/10A61P 3/04A61P 29/00A61P 35/00A61P 31/00C07H 7/02C07H 15/04A61P 19/00C07H 15/00A61P 17/00A61K 49/0002A61P 17/06A61P 19/02
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Claims
Abstract
Disclosed herein is a class of linkable tetrasaccharide compounds that includes the amino phenyl glycoside of sialyl Lewis X (SLe X ) and related analogs. These compounds have conjugatable nucleophilic groups, making them useful in preparing multimeric SLe X compositions. In particular, the disclosed SLe X compounds can be used to prepare selectin binding ligand conjugates by linking them to a reporter moiety, such as a contrast agent, a radiodiagnostic agent, or a cytotoxic or chemotherapeutic agent. The SLe X compounds and conjugates of the invention exhibit binding to selectin that is similar to native Sialyl Le X , and are, therefore, useful for diagnosing and treating selectin-mediated disorders and related conditions.
Claims
exact text as granted — not AI-modified1 . A compound comprising a sialyl Lewis X analog of formula (1)
wherein
Z is hydrogen, C 1 -C 6 acyl, or
Y is C(O), SO 2 , HNC(O), OC(O), or SC(O);
G 1 and G 2 are each independently C(R 9 ) 2 , NR 10 , O, or S;
L is alkylidene, cycloalkylidene, arylidene, or vinylidene;
R 2 is hydrogen, C(O)R 8 , SO 2 R 8 , C(S)R 8 , COCH 3 , or 14 COCH 3 ;
R 4 is hydrogen, C 1 -C 6 alkyl, aryl, arylalkyl, substituted aryl, or substituted arylalkyl;
R 3 and R 5 are each independently hydrogen, benzyl, methoxybenzyl, dimethoxybenzyl, or C 1 -C 6 acyl; and
R 1 , R 7 , R 8 , R 9 , and R 10 are each independently hydrogen, a C 1 -C 6 alkyl, an aryl, a substituted aryl, or a phenyl C 1 -C 3 alkenyl group,
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein Y is carbonyl, R 1 is hydrogen or methyl, and Z is an α-L-fucosyl having hydroxy groups that are free or blocked with a benzyl or C 1 -C 6 acyl protecting group.
3 . The compound of 1 , wherein said analog has the formula
wherein,
R is hydrogen, COCH 3 or 14 COCH 3 ;
R′ is hydrogen or acyl; and
R″ is hydrogen or methyl.
4 . The compound of claim 3 , wherein R is hydrogen, R′ is acyl, and R″ is methyl.
5 . The compound of claim 3 , wherein R is COCH 3 , and R′ and R″ are hydrogen.
6 . The compound of claim 3 , wherein R is 14 COCH 3 , and R′ and R″ are hydrogen.
7 . A selectin binding ligand conjugate comprising:
(a) a sialyl Lexis X analog (SLewis x ) moiety; (b) a reporter moiety; and (c) a linker attaching said SLewis x moiety to said reporter moiety.
8 . The conjugate of claim 7 , wherein said reporter moiety comprises a cytotoxic or therapeutic agent.
9 . The conjugate of claim 8 , wherein said reporter moiety comprises one or more cytotoxic or therapeutic agents incorporated as part of a liposome.
10 . The conjugate of claim 8 , wherein said cytotoxic or therapeutic agent comprises an antibiotic.
11 . The conjugate of claim 10 , wherein said antibiotic is selected from the group consisting of cefuroxime, linezolid and vancomycin.
12 . The conjugate of claim 8 , wherein said therapeutic agent is an anti-cancer agent.
13 . The conjugate of claim 12 , wherein said anti-cancer agent is selected from the group consisting of paclitaxel (taxol), docataxel, vinca alkaloids, dolostatins, daunomycin, doxorubicin, bleomycin, and halichondrins.
14 . The conjugate of claim 13 , wherein said anti-cancer agent comprises paclitaxel (taxol).
15 . The conjugate of claim 8 , wherein said therapeutic agent is an anti-inflammatory agent.
16 . The conjugate of claim 15 , wherein said anti-inflammatory agent is naproxen or indomethacin.
17 . The conjugate of claim 8 , wherein said therapeutic agent is an anti-oxidant.
18 . The conjugate of claim 7 , wherein said reporter moiety comprises a diagnostic imaging agent.
19 . The conjugate of claim 7 , wherein said reporter moiety comprises at least one macrocyclic or nonmacrocyclic metal chelating ligand radical.
20 . The conjugate of claim 19 , wherein said metal chelating ligand radical is chelated to a paramagnetic, super-paramagnetic, or radioactive metal.
21 . The conjugate of claim 20 , wherein said metal chelating ligand radical is chelated to a radioactive metal useful in radiotherapy.
22 . The conjugate of claim 21 , wherein said metal chelating ligand radical is chelated to a therapeutic radioactive metal selected from the group consisting of 64 Cu, 90 Y, 105 Rh, 111 In, 117m Sn, 149 Pm, 153 Sm, 161 Tb, 166 Dy, 166 Ho, 175 Yb, 177 Lu, 186/188 Re and 199 Au.
23 . The conjugate of claim 20 , wherein said metal chelating ligand radical is chelated to a radioactive metal useful in imaging or diagnosis.
24 . The conjugate of claim 23 , wherein the metal chelating ligand radical is chelated to a diagnostic radioactive metal selected from the group consisting of 64 Cu, 67 Ga, 68 Ga, 99m Tc and 111 In.
25 . The conjugate of claim 19 , wherein said metal chelating ligand radical comprises formula (B), (C) or (D):
and is chelated to a paramagnetic or radioactive lanthanide.
26 . The conjugate of claim 19 , wherein said metal chelating ligand radical comprises formula (E), (F) or (G):
wherein,
X is CH 2 or O;
Y is C1-C10 branched or unbranched alkyl, aryl, aryloxy, arylamino, arylaminoacyl, aralkyl having a C1-C10 branched or unbranched alkyl group, C1-C10 branched or unbranched hydroxy or polyhydroxyalkyl groups or polyalkoxyalkyl or polyhydroxy-polyalkoxyalkyl groups;
J is C(═O)—, OC(═O)—, SO 2 —, NC(═O)—, NC(═S)—, N(Y)—, NC(═NCH 3 )—, NC(═NH)—, N═N—, homopolyamides or heteropolyamines derived from synthetic or naturally occurring amino acids;
n is 1-100;
and said metal chelating ligand radical is chelated to radioactive 99m Tc.
27 . The conjugate of claim 18 , wherein said diagnostic imaging agent is an ultrasound contrast agent.
28 . The conjugate of claim 18 , wherein said reporter moiety comprises a phospholipid moiety in the form of a microbubble or gas filled liposome.
29 . The conjugate of claim 28 , wherein said phospholipid moiety comprises a phospholipid of formula (H):
30 . The conjugate of claim 28 , wherein said phospholipid moiety comprises a phospholipid of formula (I):
31 . The conjugate of claim 7 , wherein said SLewis x moiety comprises at least one linkable sialyl Lewis X compound of claim 1 .
32 . The conjugate of claim 7 , wherein said SLewis x moiety comprises more than one sialyl Lewis X residue.
33 . A conjugate of claim 32 , wherein said SLewis x moiety comprises four sialyl Lewis X residues.
34 . A conjugate of claim 33 comprising structure (P):
35 . A conjugate of claim 32 , further comprising more than one reporter moiety.
36 . A conjugate of claim 35 comprising structure (Q):
37 . The conjugate of claim 7 , wherein said conjugate has the formula
wherein,
X is O, S, or [CH(R 1 )] z —[N(R 6 )] w —
where z is 0, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
Y is alkylidene, cycloalkylidene, arylidene, or vinylidene;
A is —C(═O)—, —(C═S)—, or —[CH(R 1 )] t —[N(R 6 )] w —
where t is 0 to 10, inclusive;
B is O, S, or N(R′) when A is —C(═O)— or —(C═S)—, or B is —C(═O)— or —(C═S)— when A is —[CH(R 1 )] t —[N(R 6 )] w —
where t is 0 to 10, inclusive;
D is —C(═O)—, —(C═S)—, or —[CH(R)] z —[N(R 6 )] w —
where z is 0, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
E is —C(═O)—, —(C═S)—, or —[CH(R 1 )] z —[N(R 6 )] w —
where u is 0 to 10, inclusive;
q is 0 to 10, inclusive, when D is —C(═O)— or —(C═S)—, or q is
2 to 10, inclusive, when D is —[CH(R 1 )] z —[N(R 6 )] w — and z is 0, or q is
0 to 10, inclusive, when D is —[CH(R 1 )] z —[N(R 6 )] w — and z is between 2 and 10;
each w is independently 0 or 1;
m, n, o, and p are independently 1 to 3, inclusive; and
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are independently alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkoxy, aryl, or aryloxy.
38 . A pharmaceutical composition comprising the conjugate of claim 7 dissolved or dispersed in a pharmaceutically acceptable carrier.
39 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, dissolved or dispersed in a pharmaceutically acceptable carrier.
40 . A method for treating or diagnosing a selectin-mediated disorder, said method comprising administering to a patient an effective amount of the conjugate of claim 7 .
41 . A method for providing radiotherapy to a region of a patient, said method comprising administering to a patient a therapeutically effective amount of the conjugate of claim 21 .
42 . A method for imaging a region of a patient, said method comprising administering to a patient an effective amount of the conjugate of claim 23 .
43 . A method for treating or diagnosing a selectin-mediated disorder, said method comprising administering to a patient a cellular adhesion-inhibiting amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
44 . The method of claim 40 or 43 , wherein said condition is selected from the group consisting of acute or chronic inflammation, cancer, diabetes, obesity, arthritis, psoriasis, dermatitis, reperfusion injuries, rheumatism, blood clotting, atherosclerosis, thrombotic disorders, tissue rejection, leukocyte-mediated lung injury, cardiac injury, frost-bite injury, traumatic shock, septic shock, and nephritis.
45 . A method for preparing a selectin binding ligand conjugate comprising attaching the linkable sialyl Lewis X compound of claim 1 to a reporter moiety.
46 . The method of claim 45 , wherein said reporter moiety comprises a cytotoxic or therapeutic agent.
47 . The method of claim 45 , wherein said reporter moiety comprises a diagnostic imaging agent.
48 . A selectin binding ligand conjugate prepared by the method of claim 45 .
49 . A method for preparing a sialyl Lewis X analog, said method comprising the steps of:
(a) coupling together a glucosmainyl residue, a fucosyl residue, and a galactosyl residue to produce a trisaccharide; and (b) joining a sialyl residue to said trisaccharide to form a tetrasaccharide.
50 . The method of claim 49 , wherein said coupling of step (a) comprises the steps of:
(i) coupling said glucosmainyl residue with said fucosyl residue to produce a disaccharide; and (ii) coupling said disaccharide with said galactosyl residue to produce said trisaccharide.
51 . A compound prepared by the method of claim 50 .Cited by (0)
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