US5587371A
Expired / Lapsed
US
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Texaphyrin-oligonucleotide conjugates
Assignee: Pharmacyclics LLC
•
Filing: 1995-06-02
•
Granted: 1996-12-24
•
Expires: 2015-06-02
Abstract
Abstract Texaphyrins are provided for use as radiation sensitizers. Advantageous properties of texaphyrins for use as a radiation sensitizer include: i) a low redox potential which allows radiation-induced hydrated electrons to flow to texaphyrin rather than neutralizing hydroxyl radicals, allowing hydroxyl radicals to cause cellular damage, ii) a relatively stable texaphyrin radical that reacts readily to covalently modify neighboring molecules causing further cellular damage, iii) intrinsic biolocalization, and iv) indifference to the presence or absence of O2. These properties allow texaphyrins to be particularly effective for treating the hypoxic areas of solid neoplasms. Methods of treatment for an individual having a neoplasm or atheroma include the use of a texaphyrin as a radiation sensitizer and as an agent for photodynamic tumor therapy, or the use of a texaphyrin for internal and for external ionizing radiation. Novel texaphyrins are provided.
Inventors
- 👤 Jonathan L. Sessler
- 👤 Tarak D. Mody
- 👤 Gregory W. Hemmi
- 👤 Vladimir A. Kr al
- 👤 Darren Magda
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-05 03:38
CPC Classifications
A; A61; A61K; A61K51/00; A61K51/02; A61K51/04; A61K51/0474; A61K51/0485; A61K41/00; A61K41/0038; A61K41/0057; A61K41/0076; A61K47/00; A61K47/50; A61K47/51; A61K47/54; A61K47/545; A61K47/546; A61K49/00; A61K49/001; A61K49/0013; A61K49/0017; A61K49/0019; A61K49/0021; A61K49/005; A61K49/0054; A61K49/06; A61K49/08; A61K49/085; A61K49/10; A61K49/101; A61K49/106; A61K49/12; A61K49/126; A61L; A61L2/00; A61L2/02; A61P; A61P35/00; A61P35/02; A61P43/00; B; B01; B01J; B01J31/00; B01J31/16; B01J31/165; B01J31/1658; B01J31/18; B01J31/1805; B01J31/181; B01J31/1815; C; C07; C07D; C07D487/00; C07D487/22; C07H; C07H21/00; A61L2103/00; A61L2103/05; B01J2531/00; B01J2531/02; B01J2531/0238; B01J2531/0241; B01J2531/025; B01J2531/20; B01J2531/23; B01J2531/26; B01J2531/27; B01J2531/28; B01J2531/30; B01J2531/36; B01J2531/37; B01J2531/38; B01J2531/70; B01J2531/72; B01J2531/80; B01J2531/84; B01J2531/842; B01J2531/845; B01J2531/847; B01J2531/90; B01J2531/96; B01J31/02; B01J31/06; B01J31/061
Claims Analysis
Total Claims: 43
Claim 1
Independent Claim
98 words
A texaphyrin having the structure: ##STR5## wherein, M is H, a divalent metal cation or a trivalent metal cation; each of R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 is independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, saccharide, oxyaminoalkyl, carboxy, carboxyalkyl, carboxyamidealkyl, an oligonucleotide or a couple to an oligonucleotide, where at least one of R 1 , R 2 , R 3 , R 4 , R 7 and R 8 is an oligonucleotide or a couple to an oligonucleotide; and N is zero, 1 or 2.
Claim 2
Dependent Claim
98 words
A texaphyrin having the structure: ##STR5## wherein, M is H, a divalent metal cation or a trivalent metal cation; each of R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 is independently hydrogen, hydroxyl, alkyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, saccharide, oxyaminoalkyl, carboxy, carboxyalkyl, carboxyamidealkyl, an oligonucleotide or a couple to an oligonucleotide, where at least one of R 1 , R 2 , R 3 , R 4 , R 7 and R 8 is an oligonucleotide or a couple to an oligonucleotide; and N is zero, 1 or 2.
Claim 3
Dependent Claim
67 words
The texaphyrin of claim 1 where the metal cation is a divalent metal cation selected from the group consisting of Ca(II), Mn(II), Co(II), Ni(II), Zn(II), Cd(II), Hg(II), Fe(II), Sm(II) and UO 2 (II), or a trivalent metal cation selected from the group consisting of Mn(III), Co(III), Ni(III), Fe(III), Ho(III), Ce(III), Y(III), In(III), Pr(III), Nd)III), Sc(III), Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Er(III), Tm(III), Yb(III), Lu(III), La(III), and U(III).
Claim 4
Dependent Claim
11 words
The texaphyrin of claim 1 where the oligonucleotide is an oligodeoxyribonucleotide.
Claim 5
Dependent Claim
11 words
The texaphyrin of claim 1 where the oligonucleotide is an oligoribonucleotide.
Claim 6
Dependent Claim
16 words
The texaphyrin of claim 1 where the oligonucleotide is a derivatized oligonucleotide or an oligonucleotide analog.
Claim 7
Dependent Claim
21 words
The texaphyrin of claim 5 where the derivatized oligonucleotide is selected from the group consisting of methylphosphonates, phosphotriesters, phosphorothioates, and phosphoramidates.
Claim 8
Dependent Claim
12 words
The texaphyrin of claim 5 where the derivatized oligonucleotide is 2'-O-alkyl oligoribonucleotide.
Claim 9
Dependent Claim
17 words
The texaphyrin of claim 1 where the oligonucleotide has binding specificity for localization to a treatment site.
Claim 10
Dependent Claim
14 words
The texaphyrin of claim 1 where the oligonucleotide has complementary binding affinity for oncogenes.
Claim 11
Dependent Claim
14 words
The texaphyrin of claim 1 where the oligonucleotide has complementary binding affinity for DNA.
Claim 12
Dependent Claim
14 words
The texaphyrin of claim 1 where the oligonucleotide has complementary binding affinity for RNA.
Claim 13
Dependent Claim
17 words
The texaphyrin of claim 1 where the oligonucleotide has complementary binding affinity for a targeted intracellular mRNA.
Claim 14
Dependent Claim
12 words
The texaphyrin of claim 1 where the oligonucleotide is an antisense oligonucleotide.
Claim 15
Dependent Claim
24 words
The texaphyrin of claim 1 wherein R 1 alkyl or hydroxyalkyl, and each of R 2 , R 3 and R 4 is alkyl.
Claim 16
Dependent Claim
25 words
The texaphyrin of claim 1 where one of R 3 , R 7 and R 8 is an oligonucleotide or a couple to an oligonucleotide.
Claim 17
Dependent Claim
24 words
The texaphyrin of claim 1 wherein the oligonucleotide or couple to oligonucleotide is O(CH 2 ) n CO-oligonucleotide where n is 1 to 7.
Claim 18
Dependent Claim
17 words
The texaphyrin of claim 1 where the texaphyrin is attached to the 5' end of the oligonucleotide.
Claim 19
Dependent Claim
17 words
The texaphyrin of claim 1 where the texaphyrin is attached to the 3' end of the olignucleotide.
Claim 20
Dependent Claim
17 words
The texaphyrin of claim 1 where the texaphyrin is attached to the oligonucleotide at an internal position.
Claim 21
Dependent Claim
12 words
The texaphyrin of claim 5 where the derivatized oligonucleotide is a phosphorothioate.
Claim 22
Dependent Claim
12 words
The texaphyrin of claim 5 where the derivatized oligonucleotide is a phosphoramidate.
Claim 23
Dependent Claim
12 words
The texaphyrin of claim 5 where the derivatized oligonucleotide is 2'-O-substituted oligoribonucleotide.
Claim 24
Dependent Claim
12 words
The texaphyrin of claim 7 where the derivatized oligonucleotide is 2'-O-methyl oligoribonucleotide.
Claim 25
Dependent Claim
15 words
The texaphyrin of claim 1 where the oligonucleotide has complementary binding affinity for viral RNA.
Claim 26
Dependent Claim
15 words
The texaphyrin of claim 1 where the oligonucleotide has complementary binding affinity for retroviral RNA.
Claim 27
Dependent Claim
16 words
The texaphyrin of claim 1 where the oligonucleotide has complementary binding affinity for bacterial nucleic acids.
Claim 28
Dependent Claim
16 words
The texaphyrin of claim 1 where the oligonucleotide has complementary binding affinity for bacterial ribosomal RNA.
Claim 29
Dependent Claim
14 words
The texaphyrin of claim 5 where the derivatized oligonucleotide is a peptide nucleic acid.
Claim 30
Dependent Claim
32 words
The texaphyrin of claim 1 where two of R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 are oligonucleotides or couples to oligonucleotides.
Claim 31
Dependent Claim
29 words
The texaphyrin of claim 29 where R 3 is an oligonucleotide or a couple to an oligonucleotide, and R 8 is an oligonucleotide or a couple to an oligonucleotide.
Claim 32
Dependent Claim
36 words
The texaphyrin of claim 1 where R 1 is CH 2 CH 2 CH 2 OH, each of R 2 and R 3 is CH 2 CH 3 , and R 4 is CH 3 .
Claim 33
Dependent Claim
28 words
The texaphyrin of claim 31 where R 7 is OCH 2 CH 2 CH 2 OH and R 8 is an oligonucleotide or a couple to an oligonucleotide.
Claim 34
Dependent Claim
33 words
The texaphyrin of claim 31 where R 7 is O(CH 2 CH 2 O) 2 CH 2 CH 2 OCH 3 and R 8 is an oligonucleotide or a couple to an oligonucleotide.
Claim 35
Dependent Claim
59 words
The texaphyrin of claim 1 where the oxyhydroxyalkyl is C.sub.(n-x) H.sub.((2n+1)-2x) O x O y or OC.sub.(n-x) H.sub.((2n+1)-2x) O x O y where n is a positive integer from 1 to 10; x is zero or a positive integer less than or equal to n; and y is zero or a positive integer less than or equal to ((2n+1)-2x).
Claim 36
Dependent Claim
197 words
The texaphyrin of claim 1 where the oxyhydroxyalkyl or saccharide is C n H.sub.((2n+1)-q)O y R a q , OC n H.sub.((2n+1)-q) O y R a q or (CH 2 ) n CO 2 R a where n is a positive integer from 1 to 10; y is zero or a positive integer less than or equal to ((2n+1)-q); q is zero or a positive integer less than or equal to (2n+1); and R a is independently H, alkyl, hydroxyalkyl, saccharide, C.sub.(m-w) H.sub.((2m+1)-2w) O w O z , O 2 CC.sub.(m-w) H.sub.((2m+1)-2w) O w O z or N(R)OCC.sub.(m-w) H.sub.((2m+1)-2w) O w O z , where m is a positive integer from 1 to 10, w is zero or a positive integer less than or equal to m, z is zero or a positive integer less than or equal to ((2m+1)-2w), and R is H, alkyl, hydroxyalkyl, or C m H.sub.((2m+1)-r) O z R b r where m is a positive integer from 1 to 10, z is zero or a positive integer less than ((2m+1)-r), r is zero or a positive integer less than or equal to 2m+1, and R b is H, alkyl, hydroxyalkyl, or saccharide.
Claim 37
Dependent Claim
175 words
The texaphyrin of claim 1 where the carboxyamidealkyl is (CH 2 ) n CONHR a , O(CH 2 ) n CONHR a , (CH 2 ) n CON(R a ) 2 , or O(CH 2 ) n CON(R a ) 2 where n is a positive integer from 1 to 10; R a is independently H, alkyl, hydroxyalkyl, saccharide, C.sub.(m-w) H.sub.((2m+1)-2w) O w O z , O 2 CC.sub.(m-w) H.sub.((2m+1)-2w) O w O z or N(R)OCC.sub.(m-w) H.sub.((2m+1)-2w) O w O z , where m is a positive integer from 1 to 10, w is zero or a positive integer less than or equal to m, z is zero or a positive integer less than or equal to ((2m+1)-2w), and R is H, alkyl, hydroxyalkyl, or C m H.sub.((2m+1)-r) O z R b r where m is a positive integer from 1 to 10, z is zero or a positive integer less than ((2m+1)-r), r is zero or a positive integer less than or equal to 2m+1, and R b is H, alkyl, hydroxyalkyl, or saccharide.
Claim 38
Dependent Claim
225 words
The texaphyrin of claim 1 where the carboxyalkyl is C n H.sub.((2n+1)-q) O y R c q or OC n H.sub.(2n+1)-q) O y R c q where n is a positive integer from 1 to 10; y is zero or a positive integer less than or equal to ((2n+1)-q); q is zero or a positive integer less than or equal to (2n+1); and R c is (CH 2 ) n CO 2 R d , (CH 2 ) n CONHR d , or (CH 2 ) n CON(R d ) 2 where n is a positive integer from 1 to 10, and R d is H, alkyl, hydroxyalkyl, saccharide, C.sub.(m-w) H.sub.((2m+1)-2w) O w O z , O 2 CC.sub.(m-w) H.sub.((2m+1)-2w) O w O z or N(R)OCC.sub.(m-w) H.sub.((2m+1)-2w) O w O z , where m is a positive integer from 1 to 10, w is zero or a positive integer less than or equal to m, z is zero or a positive integer less than or equal to ((2m+1)-2w), and R is H, alkyl, hydroxyalkyl, or C m H.sub.((2m+1)-r) O z R b r where m is a positive integer from 1 to 10, z is zero or a positive integer less than ((2m+1)-r), r is zero or a positive integer less than or equal to 2m+1, and R b is H, alkyl, hydroxyalkyl, or saccharide.
Claim 39
Dependent Claim
13 words
The texaphyrin of claim 1 where the metal cation is a lanthanide metal.
Claim 40
Dependent Claim
13 words
The texaphyrin of claim 1 where the metal cation is a paramagnetic ion.
Claim 41
Dependent Claim
13 words
The texaphyrin of claim 1 where the metal cation is a diamagnetic ion.
Claim 42
Dependent Claim
79 words
The texaphyrin of claim 1 wherein R 1 is CH 2 CH 3 or CH 2 CH 2 CH 2 OH; each of R 2 and R 3 is CH 2 CH 3 ; R 4 is CH 3 ; R 7 is H, OCH 3 , OCH 2 CH 2 CH 2 OH or O(CH 2 CH 2 O) n CH 3 where n is 1-7; and R 8 is an oligonucleotide or a couple to an oligonucleotide.
Claim 43
Dependent Claim
9 words
A pharmaceutical perparation comprising the texaphyrin of claim 1.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1999-12-24 | 2000-06-24 | 2000-12-24 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2003-12-24 | 2004-06-24 | 2004-12-24 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2007-12-24 | 2008-06-24 | 2008-12-24 | $7700.00 | Window Closed / Lapsed |