Prevention and treatment of cardiovascular pathologies with tamoxifen analogues

• US 6,197,789 B1
• Filed: 12/05/1997
• Issued: 03/06/2001
• Est. Priority Date: 06/07/1995
• Status: Expired due to Term

• Current Assignee: Boston Scientific Scimed, Inc. (Boston Scientific Corporation), UAB Research Foundation (University of Alabama System)
• Original Assignee: NeoRx Corporation
• Inventors: Grainger, David J., Kunz, Lawrence L., Metcalfe, James C., Schroff, Robert W.
• Primary Examiner(s): Criares, Theodore J.
• Application Number:
  US08/973,570
• Time in Patent Office: 1,187 Days
• Field of Search: 514/319, 514/324, 514/422, 514/428, 514/444, 514/448, 514/651, 514/866
• US Class Current: 514/319
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/38 having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: G01N 2800/32 Cardiovascular disorders
• CPC Class Codes: G01N 2800/324 Coronary artery diseases, e.g. angina pectoris, myocardial infarction

Abstract

A method for treating or preventing cardiovascular pathologies by administering a compound of the formula (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, 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 elevate the level of TGF-beta to treat and/or prevent conditions such as atherosclerosis, thrombosis, myocardial infarction, and stroke is provided. Useful compounds include idoxifene, toremifene or salts thereof. Further provided is a method for identifying an agent that elevates the level of TGF-beta. 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).

Claims

1. A method of treating diabetics at risk of, or afflicted with, vascular disease, comprising:

administering an amount of tamoxifen or a structural analog thereof effective to inhibit the proliferation of vascular tissue.

2. The method of claim 1 wherein the structural analog of tamoxifen is idoxifene, 4-iodotamoxifen, 3-iodotamoxifen, raloxifene, droloxifene, toremifene, or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 wherein the analog is idoxifene, 4-iodotamoxifen, 3-iodotamoxifen, droloxifene, toremifene, or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 wherein the diabetic has an abnormal lipid profile.

5. A kit comprising, separately packaged, a catheter adapted for the local delivery of a therapeutic agent to a site in the lumen of a mammalian vessel and a unit dosage of a therapeutic agent of formula (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, R⁴ 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, wherein the unit dosage is effective to inhibit pathological activity of the smooth muscle cells at said site.

6. The kit of claim 5 wherein the therapeutic agent of formula (I) is idoxifene, toremifene, or a pharmaceutically acceptable salt thereof.

8. The kit of claim 5 wherein the catheter is adapted to deliver the unit dosage form to an arterial lesion.

9. The kit of claim 5 wherein the catheter is adapted to deliver the unit dosage form to a vessel site which has been subjected to coronary angioplasty.

10. The kit of claim 5 wherein the agent is idoxifene or a pharmaceutically acceptable salt thereof.

11. The kit of claim 5 wherein the agent is toremifene, or a pharmaceutically acceptable salt thereof.

12. The kit of claim 5 wherein the agent increases the level of TGF-beta.

7. A kit comprising, separately packaged, a catheter adapted for the local delivery of a therapeutic agent to a site in the lumen of a mammalian vessel and a unit dosage of droloxifene and pharmaceutically acceptable salts thereof, wherein the unit dosage is effective to inhibit pathological activity of the smooth muscle cells at said site.

13. An intravascular stent comprising an amount of a compound of formula (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, R³ is ethyl or chloroethyl, R⁴ is H or together with R³ is —

CH₂—

CH₂—

or —

S—

, R⁵ is I, OH, O(C₁-C₄)alkyl or H and R⁶ is I, O(C₁-C₄)alkyl or H;

or a pharmaceutically acceptable salt thereof, effective to inhibit stenosis or reduce restenosis of a mammalian vessel following placement of the stent in said vessel.

16. The stent of claim 13, 14, or 15, wherein a cytostatic amount is administered.

17. The stent of claim 13, 14, or 16, wherein R³ is not ethyl when R⁴, R⁵ and R⁶ are H.

14. An intravascular stent comprising an amount of a compound of formula (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—

, R⁵ is I, OH, O(C₁-C₄)alkyl or H and R⁶ is I, O(C₁-C₄)alkyl or H;

or a pharmaceutically acceptable salt thereof;

effective to inhibit stenosis or reduce restenosis of a mammalian vessel following placement of the stent in said vessel.

15. An intravascular stent comprising an amount of a compound of formula (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 R³is —

CH₂—

CH₂—

or —

S—

, R⁵ is I, OH or O(C₁-C₄)alkyl and R⁶ is I, O(C₁-C₄)alkyl or H;

or a pharmaceutically acceptable salt thereof;

effective to inhibit stenosis or reduce restenosis of a mammalian vessel following placement of the stent in said vessel.