Treatment for atherosclerosis and other cardiovascular and inflammatory diseases

• US 5,877,203 A
• Filed: 10/17/1996
• Issued: 03/02/1999
• Est. Priority Date: 10/30/1992
• Status: Expired due to Term

• Current Assignee: Emory University
• Original Assignee: Emory University
• Inventors: Alexander, R. Wayne, Offermann, Margaret K., Medford, Russell M.
• Primary Examiner(s): Lambkin, Deborah C.
• Application Number:
  US08/722,438
• Time in Patent Office: 866 Days
• Field of Search: 514/423, 514/599, 514/712, 514/707, 514/330, 514/212, 514/551
• US Class Current: 514/423
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/145 having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2) isothiourea A61K31/155
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/325 Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof thiurams A61K31/145
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• 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 2333/70503 Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
• CPC Class Codes: G01N 2333/7056 Selectin superfamily, e.g. LAM-1, GlyCAM, ELAM-1, PADGEM
• CPC Class Codes: G01N 2800/323 Arteriosclerosis, Stenosis
• CPC Class Codes: G01N 33/6872 Intracellular protein regulatory factors and their receptors, e.g. including ion channels

Abstract

Dithiocarboxylates, and in particular, dithiocarbamates, block the induced expression of the endothelial cell surface adhesion molecule VCAM-1, and are therefor useful in the treatment of cardiovascular disease, including atherosclerosis, post-angioplasty restenosis, coronary artery diseases, and angina, as well as noncardiovascular inflammatory diseases that are mediated by VCAM-1.

Claims

1. A method for treating inflammatory diseases by VCAM-1 expression in human cells comprising administering an effective amount of a dithiocarbamate of the formula:

space="preserve" listing-type="equation">R.sup.1 SC(S)NR.sup.2 R.sup.3

wherein R¹ is H, sodium, potassium, or NR⁴ R⁵ R⁶ R⁷, wherein R⁴, R⁵, R⁶, and R⁷ are independently hydrogen, C_1-6 linear, branched, or cyclic alkyl, hydroxy(C_1-6)alkyl, or aryl, and

R² and R³ are independently C_1-10 linear, branched or cyclic alkyl;

--(CHOH)_n (CH₂)_n OH, wherein n is independently 0-6;

--(CH₂)_n CO₂ R¹, --(CH₂)_n CO₂ R⁸ ;

hydroxy(C_1-6)alkyl--, or R² and R³ together constitute a bridge of the formula --(CH₂)_m --, wherein m is 3-6, and wherein R₈ is alkyl, aryl, alkylaryl, or aralkyl or its pharmaceutically acceptable salt.

2. The method of claim 1, wherein the dithiocarbamate is selected from the group consisting of sodium pyrrolidine-N-carbodithioate, sodium N-methyl-N-carboxymethyl-N-carbodithioate, trisodium N,N-di(carboxymethyl)-N-carbodithioate, sodium N-methyl-D-glucamine-N-carbodithioate, sodium N,N-diethyl-N-carbodithioate (sodium diethyldithiocarbamate), and sodium N,N-diisopropyl-N-carbodithioate.

3. The method of claim 1, wherein the dithiocarbamate is sodium pyrrolidine-N-carbodithioate.

4. The method of claim 1, wherein R² is a C_1-10 linear, branched or cyclic alkyl group.

5. The method of claim 1, wherein R² is --(CHOH)_n (CH₂)_n OH, wherein n is independently 0-6.

6. The method of claim 1, wherein R² is selected from the group consisting of --(CH₂)_n CO₂ R¹, --(CH₂)_n CO₂ R⁸ ;

and hydroxy(C_1-6)alkyl--, and wherein R⁸ is alkyl, aryl, alkylaryl, or aralkyl.

7. The method of claim 1, wherein R² and R³ together constitute a bridge of the formula --(CH₂)_m --, wherein m is 4.

8. The method of claim 1, wherein the dithiocarbamate is administered in a dosage of between 0.5 and 500 mg/kg body weight.

9. The method of claim 1, wherein the dithiocarbamate is administered by perfusion balloon catheter.

10. The method of claim 1 wherein the dithiocarbamate is in the form of a pharmaceutically acceptable salt.

11. The method of claim 1, wherein R⁸ is methyl, propyl or butyl.

12. The method of claim 1, wherein m is 3-6.

13. The method of claim 1, wherein the dithiocarbamate is administered intravenously.

14. The method of claim 1, wherein the dithiocarbamate is administered orally.