Patent US2602914A successfully refreshed from Google Patents.
Patent US5770609A successfully refreshed from Google Patents.
US5770609A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Prevention and treatment of cardiovascular pathologies
Assignee: Poniard Pharmaceuticals Inc
•
Filing: 1995-06-07
•
Granted: 1998-06-23
•
Expires: 2015-06-07
Abstract
Abstract A method for treating or preventing cardiovascular pathologies by administering a compound of the formula (I): <IMAGE> (I) wherein Z is C=O or a covalent bond; Y is H or O(C1-C4)alkyl, R1 and R2 are individually (C1-C4)alkyl or together with N are a saturated heterocyclic group, R3 is ethyl or chloroethyl, R4 is H or together with R3 is -CH2-CH2- or -S-, R5 is I, O(C1-C4)alkyl or H and R6 is I, O(C1-C4)alkyl or H with the proviso that when R4, R5, and R6 are H, R3 is not ethyl; or a pharmaceutically acceptable salt thereof, effective to activate or stimulate production of TGF-beta to treat and/or prevent conditions such as atherosclerosis, thrombosis, myocardial infarction, and stroke is provided. Useful compounds include idoxifene and salts thereof. Further provided is a method for identifying a compound that is a TGF-beta activator or production stimulator is provided. Another embodiment of the invention is an assay or kit to determine TGF-beta in vitro. Also provided is a therapeutic method comprising inhibiting smooth muscle cell proliferation associated with procedural vascular trauma employing the administration of tamoxifen or structural analogs thereof, including compounds of formula (I).
Inventors
- 👤 David J. Grainger
- 👤 James C. Metcalfe
- 👤 Lawrence L. Kunz
- 👤 Robert W. Schroff
- 👤 Peter L. Weissberg
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 04:45
CPC Classifications
A; A61; A61K; A61K9/00; A61K9/0012; A61K9/0019; A61K9/0024; A61K31/00; A61K31/13; A61K31/135; A61K31/138; A61K31/33; A61K31/335; A61K31/337; A61K31/38; A61K31/395; A61K31/40; A61K31/4025; A61K31/403; A61K31/4035; A61K31/407; A61K31/70; A61K31/715; A61K47/00; A61K47/50; A61K47/51; A61K47/68; A61K47/6801; A61K47/6803; A61K47/6807; A61K47/6809; A61K47/6811; A61K47/6817; A61K47/6831; A61K47/6835; A61K47/6843; A61K47/69; A61K47/6921; A61K47/6927; A61K47/6929; A61K47/6931; A61K47/6935; A61K47/6937; A61K47/6957; C; C07; C07K; C07K14/00; C07K14/435; C07K14/705; C07K14/71; C07K16/00; C07K16/18; C07K16/22; G; G01; G01N; G01N2800/00; G01N2800/32
Claims Analysis
Total Claims: 60
Claim 1
Independent Claim
117 words
A therapeutic method comprising inhibiting smooth muscle cell (SMC) proliferation associated with procedural vascular trauma comprising the systemic administration to a mammal subjected to said procedure, an effective cytostatic SMC proliferative inhibitory amount of a compound of formula (1): ##STR3## wherein Z is C═O or a covalent bond; Y is H or O(C 1 -C 4 )alkyl, R 1 and R 2 are individually (C 1 -C 4 )alkyl or together with N are a saturated heterocyclic group, R 3 is ethyl or chloroethyl, R 4 is H, R 5 is I, O(C 1 -C 4 )alkyl or H and R 6 is I, O(C 1 -C 4 )alkyl or H; or a pharmaceutically acceptable salt thereof.
Claim 2
Dependent Claim
117 words
A therapeutic method comprising inhibiting smooth muscle cell (SMC) proliferation associated with procedural vascular trauma comprising the systemic administration to a mammal subjected to said procedure, an effective cytostatic SMC proliferative inhibitory amount of a compound of formula (1): ##STR3## wherein Z is C═O or a covalent bond; Y is H or O(C 1 -C 4 )alkyl, R 1 and R 2 are individually (C 1 -C 4 )alkyl or together with N are a saturated heterocyclic group, R 3 is ethyl or chloroethyl, R 4 is H, R 5 is I, O(C 1 -C 4 )alkyl or H and R 6 is I, O(C 1 -C 4 )alkyl or H; or a pharmaceutically acceptable salt thereof.
Claim 3
Dependent Claim
33 words
The method of claim 1 wherein the procedural vascular trauma is due to organ transplantation, vascular surgery, transcatheter vascular therapy, vascular grafting, placement of a vascular shunt or placement of an intravascular stent.
Claim 4
Dependent Claim
19 words
The method of claim 1 wherein the compound of formula (I) is tamoxifen or a pharmaceutically acceptable salt thereof.
Claim 5
Dependent Claim
22 words
The method of claim 1 wherein the compound of formula (I) is idoxifene, 4-iodotamoxifen, 3-iodotamoxifen, toremifene, or a pharmaceutically acceptable salt thereof.
Claim 6
Dependent Claim
19 words
The method of claim 4 wherein the compound of formula (I) is idoxifene or a pharmaceutically acceptable salt thereof.
Claim 7
Dependent Claim
13 words
The method of claim 1 wherein the administration is to a human patient.
Claim 8
Dependent Claim
21 words
The method of claim 6 wherein the administration is before or after said procedure, or both before and after said procedure.
Claim 9
Dependent Claim
15 words
The method of claim 6 wherein the administration is in a series of spaced doses.
Claim 10
Dependent Claim
10 words
The method of claim 6 wherein the administration is parenteral.
Claim 11
Dependent Claim
10 words
The method of claim 6 wherein the administration is oral.
Claim 12
Dependent Claim
19 words
The method of claim 1 wherein the compound of formula (I) is administered via a sustained release dosage form.
Claim 13
Dependent Claim
17 words
The method of claim 1 wherein the administration is localized at the site of the vascular trauma.
Claim 14
Dependent Claim
134 words
A therapeutic method comprising inhibiting vascular smooth muscle cell proliferation associated with procedural vascular trauma comprising administration to a mammal subjected to said procedural trauma an effective antiproliferative amount of a compound of formula (I): ##STR4## wherein Z is C═O or a covalent bond; Y is H or O(C 1 -C 4 )alkyl, R 1 and R 2 are individually (C 1 -C 4 )alkyl or together with N are a saturated heterocyclic group, R 3 is ethyl or chloroethyl, R 4 is H, R 5 is I, O(C 1 -C 4 )alkyl or H and R 6 is I, O(C 1 -C 4 )alkyl or H with the proviso that when R 4 , R 5 , and R 6 are H, R 3 is not ethyl; or a pharmaceutically acceptable salt thereof.
Claim 15
Dependent Claim
134 words
A therapeutic method comprising inhibiting vascular smooth muscle cell proliferation associated with procedural vascular trauma comprising administration to a mammal subjected to said procedural trauma an effective antiproliferative amount of a compound of formula (I): ##STR4## wherein Z is C═O or a covalent bond; Y is H or O(C 1 -C 4 )alkyl, R 1 and R 2 are individually (C 1 -C 4 )alkyl or together with N are a saturated heterocyclic group, R 3 is ethyl or chloroethyl, R 4 is H, R 5 is I, O(C 1 -C 4 )alkyl or H and R 6 is I, O(C 1 -C 4 )alkyl or H with the proviso that when R 4 , R 5 , and R 6 are H, R 3 is not ethyl; or a pharmaceutically acceptable salt thereof.
Claim 16
Dependent Claim
22 words
The method of claim 14 wherein the compound of formula (I) is idoxifene, 4-iodotamoxifen, 3-iodotamoxifen, toremifene, or a pharmaceutically acceptable salt thereof.
Claim 17
Dependent Claim
19 words
The method of claim 14 wherein the compound of formula (I) is idoxifene or a pharmaceutically acceptable salt thereof.
Claim 18
Dependent Claim
13 words
The method of claim 13 wherein the administration is to a human patient.
Claim 19
Dependent Claim
21 words
The method of claim 16 wherein the administration is before or after said procedure, or both before and after said procedure.
Claim 20
Dependent Claim
15 words
The method of claim 16 wherein the administration is in a series of spaced doses.
Claim 21
Dependent Claim
10 words
The method of claim 16 wherein the administration is parenteral.
Claim 22
Dependent Claim
10 words
The method of claim 16 wherein the administration is oral.
Claim 23
Dependent Claim
10 words
The method of claim 16 wherein the administration is systemic.
Claim 24
Dependent Claim
19 words
The method of claim 13 wherein the compound of formula (I) is administered via a sustained release dosage form.
Claim 25
Dependent Claim
17 words
The method of claim 13 wherein the administration is localized at the site of the vascular trauma.
Claim 26
Dependent Claim
142 words
A therapeutic method comprising treating non-aortal procedural vascular trauma comprising administering to a mammal, subjected to said procedural vascular trauma, an effective cytostatic antiproliferative amount of a compound of formula (I): ##STR5## wherein Z is a covalent bond; Y is H or O(C 1 -C 4 )alkyl, R 1 and R 2 are individually (C 1 -C 4 )alkyl or together with N are a saturated heterocyclic group, R 3 is ethyl or chloroethyl, R 4 is H or together with R 3 is --CH 2 --CH 2 -- or --S--, R 5 is I, OH, O(C 1 -C 4 )alkyl or H and R 6 is I, O(C 1 -C 4 )alkyl or H with the proviso that when R 4 , R 5 , and R 6 are H, R 3 is not ethyl; or a pharmaceutically acceptable salt thereof.
Claim 27
Dependent Claim
142 words
A therapeutic method comprising treating non-aortal procedural vascular trauma comprising administering to a mammal, subjected to said procedural vascular trauma, an effective cytostatic antiproliferative amount of a compound of formula (I): ##STR5## wherein Z is a covalent bond; Y is H or O(C 1 -C 4 )alkyl, R 1 and R 2 are individually (C 1 -C 4 )alkyl or together with N are a saturated heterocyclic group, R 3 is ethyl or chloroethyl, R 4 is H or together with R 3 is --CH 2 --CH 2 -- or --S--, R 5 is I, OH, O(C 1 -C 4 )alkyl or H and R 6 is I, O(C 1 -C 4 )alkyl or H with the proviso that when R 4 , R 5 , and R 6 are H, R 3 is not ethyl; or a pharmaceutically acceptable salt thereof.
Claim 28
Dependent Claim
21 words
The method of claim 24 wherein the administration is before or after said procedure, or both before and after said procedure.
Claim 29
Dependent Claim
15 words
The method of claim 24 wherein the administration is in a series of spaced doses.
Claim 30
Dependent Claim
10 words
The method of claim 24 wherein the administration is parenteral.
Claim 31
Dependent Claim
10 words
The method of claim 24 wherein the administration is oral.
Claim 32
Dependent Claim
10 words
The method of claim 24 wherein the administration is systemic.
Claim 33
Dependent Claim
16 words
The method of claim 24 wherein the compound is administered via a sustained release dosage form.
Claim 34
Dependent Claim
17 words
The method of claim 24 wherein the administration is localized at the site of the vascular trauma.
Claim 35
Dependent Claim
16 words
The method of claim 24 wherein the compound is droloxifene, or a pharmaceutically acceptable salt thereof.
Claim 36
Dependent Claim
16 words
The method of claim 24 wherein the compound is toremifene, or a pharmaceutically acceptable salt thereof.
Claim 37
Dependent Claim
16 words
The method of claim 24 wherein the compound is idoxifene, or a pharmaceutically acceptable salt thereof.
Claim 38
Dependent Claim
18 words
The method of claim 1 or 13 wherein the compound is toremifene, or a pharmaceutically acceptable salt thereof.
Claim 39
Dependent Claim
16 words
The method of claim 1, 13 or 24 wherein the compound increases the level of TGF-beta.
Claim 40
Dependent Claim
29 words
The method of claim 1, 13 or 24 wherein the administration increases the level of active TGF-beta relative to the level of active TGF beta prior to said administration.
Claim 41
Dependent Claim
28 words
The method of claim 1, 13 or 24 wherein the administration increases the level of latent TGF-beta relative to the level of latent TGF-beta prior to said administration.
Claim 42
Dependent Claim
21 words
The method of claim 1, 13 or 24 wherein the administration of the therapeutic agent increases the level of TGF-beta MRNA.
Claim 43
Dependent Claim
28 words
The method of claim 1, 13 or 24 wherein the administration of the therapeutic agent increases the conversion of the latent form of TGF-beta to the active form.
Claim 44
Dependent Claim
20 words
The method of claim 1, 13 or 24 wherein the administration of the therapeutic agent increases the bioavailability of TGF-beta.
Claim 45
Dependent Claim
19 words
The method of claim 1, 13 or 24 wherein the administration is before, during or after said vascular trauma.
Claim 46
Dependent Claim
11 words
The method of claim 24 wherein the procedure is vessel anosthomosis.
Claim 47
Dependent Claim
11 words
The method of claim 24 wherein the procedure is organ transplantation.
Claim 48
Dependent Claim
10 words
The method of claim 44 wherein the organ is kidney.
Claim 49
Dependent Claim
11 words
The method of claim 44 wherein the organ is a liver.
Claim 50
Dependent Claim
11 words
The method of claim 24 wherein the procedure is a biopsy.
Claim 51
Dependent Claim
10 words
The method of claim 24 wherein the procedure is thrombectomy.
Claim 52
Dependent Claim
13 words
The method of claim 24 wherein the procedure is a vascular bypass graft.
Claim 53
Dependent Claim
11 words
The method of claim 24 wherein the cells comprise ocular tissue.
Claim 54
Dependent Claim
132 words
A therapeutic method comprising inhibiting vascular smooth muscle cell proliferation comprising administering to a mammal an effective cytostatic antiproliferative amount of a compound of formula (I): ##STR6## wherein Z is a covalent bond; Y is H or O(C 1 -C 4 )alkyl, R 1 and R 2 are individually (C 1 -C 4 )alkyl or together with N are a saturated heterocyclic group, R 3 is ethyl or chloroethyl, R 4 is H or together with R 3 is --CH 2 --CH 2 -- or --S--, R 5 is I, OH, O(C 1 -C 4 )alkyl or H and R 6 is I, O(C 1 -C 4 )alkyl or H; or a pharmaceutically acceptable salt thereof, wherein the administration is by placement of a vascular shunt or intravascular stent comprising said compound.
Claim 55
Dependent Claim
132 words
A therapeutic method comprising inhibiting vascular smooth muscle cell proliferation comprising administering to a mammal an effective cytostatic antiproliferative amount of a compound of formula (I): ##STR6## wherein Z is a covalent bond; Y is H or O(C 1 -C 4 )alkyl, R 1 and R 2 are individually (C 1 -C 4 )alkyl or together with N are a saturated heterocyclic group, R 3 is ethyl or chloroethyl, R 4 is H or together with R 3 is --CH 2 --CH 2 -- or --S--, R 5 is I, OH, O(C 1 -C 4 )alkyl or H and R 6 is I, O(C 1 -C 4 )alkyl or H; or a pharmaceutically acceptable salt thereof, wherein the administration is by placement of a vascular shunt or intravascular stent comprising said compound.
Claim 56
Dependent Claim
20 words
The method of claim 51 wherein the compound is droloxifene, raloxifene, toremifene, tamoxifen, idoxifene, or a pharmaceutically acceptable salt thereof.
Claim 57
Dependent Claim
19 words
The method of claim 51 wherein the shunt or stent matrix is impregnated with the compound of formula (I).
Claim 58
Dependent Claim
19 words
The method of claim 53 wherein the shunt or stent comprises a coating incorporating said compound of formula (I).
Claim 59
Dependent Claim
19 words
The method of claim 51 wherein the shunt or stent comprises a coating incorporating said compound of formula (I).
Claim 60
Dependent Claim
16 words
The method of claim 53, 54, or 55 wherein said matrix or said coating is biodegradable.
References Cited (Backward Citations)
US32944A
Cited
US3010965A
Cited
US2914563A
Cited
US3168565A
Cited
GB1015787A
Cited
US4536516A
Cited
US3288806A
Cited
US3634517A
Cited
US3940422A
Cited
US4070484A
Cited
USRE32944E
Cited
US4093709A
Cited
US4323707A
Cited
US4133814A
Cited
US4230862A
Cited
US4235988A
Cited
US4307111A
Cited
US5324736A
Cited
US5098903A
Cited
US4442119A
Cited
US5332584A
Cited
US4675189A
Cited
US5047431A
Cited
US4418068A
Cited
US4380635A
Cited
US5015666A
Cited
US4879315A
Cited
EP0095875B1
Cited
US4696949A
Cited
US5491173A
Cited
US4996225A
Cited
US4512762A
Cited
US5226430A
Cited
US5284763A
Cited
US4824436A
Cited
US4826672A
Cited
US5316766A
Cited
US4859585A
Cited
US4962091A
Cited
US5314679A
Cited
US4839155A
Cited
EP0260066B1
Cited
US5120535A
Cited
US5075321A
Cited
US4968350A
Cited
US4973755A
Cited
US5114719A
Cited
US5527337A
Cited
US4835002A
Cited
US5221620A
Cited
US5008279A
Cited
US4929602A
Cited
US4997652A
Cited
US5213580A
Cited
US5208019A
Cited
US5066789A
Cited
US5395842A
Cited
US5393785A
Cited
US5340925A
Cited
US5268358A
Cited
US5304541A
Cited
US5032679A
Cited
US5380716A
Cited
US5545409A
Cited
US5356713A
Cited
US5364632A
Cited
US5026537A
Cited
US5248764A
Cited
US5112305A
Cited
US5242397A
Cited
US5043335A
Cited
US4990538A
Cited
US5597578A
Cited
US5176617A
Cited
US5059166A
Cited
US5049132A
Cited
US5199939B1
Cited
US5199939A
Cited
US5328471A
Cited
US5140012A
Cited
US5166143A
Cited
US5189046A
Cited
US5189212A
Cited
US5192525A
Cited
US5219548A
Cited
US5238714A
Cited
US5053033A
Cited
US5180366A
Cited
US5362424A
Cited
US5308622A
Cited
US5102402A
Cited
US5171217A
Cited
US5280016A
Cited
US5254594A
Cited
US5116864A
Cited
US5213576A
Cited
US5296492A
Cited
US5229495A
Cited
US5216126A
Cited
US5185260A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 2001-06-22 | 2001-12-22 | 2002-06-23 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2005-06-22 | 2005-12-22 | 2006-06-23 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2009-06-22 | 2009-12-22 | 2010-06-23 | $7700.00 | Window Closed / Lapsed |