Treatment for atherosclerosis and other cardiovascular and inflammatory diseases

• US 5,783,596 A
• Filed: 06/07/1995
• Issued: 07/21/1998
• Est. Priority Date: 10/30/1992
• Status: Expired due to Term

• Current Assignee: Emory University
• Original Assignee: Emory University
• Inventors: Parthasarathy, Sampath, Medford, Russell M., Alexander, R. Wayne, Offermann, Margaret K.
• Primary Examiner(s): O SULLIVAN, PETER G
• Application Number:
  US08/477,881
• Time in Patent Office: 1,140 Days
• Field of Search: 424/9.1, 424/9.2, 436/71, 436/86, 436/129, 514/18, 514/423, 514/478, 514/479, 514/484, 514/485, 514/487, 514/488, 514/489, 514/506, 514/513, 514/824, 514/825, 514/826, 514/861, 514/863, 530/331, 548/431, 558/230, 558/235, 564/76, 568/21, 568/25
• 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 31/265 of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
• 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: C07C 333/04 having nitrogen atoms of thiocarbamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 333/08 having nitrogen atoms of thiocarbamic groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 333/16 Salts of dithiocarbamic acids
• CPC Class Codes: C07D 295/21 Radicals derived from sulfur analogues of carbonic acid
• 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 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 2800/323 Arteriosclerosis, Stenosis
• CPC Class Codes: G01N 33/68 involving proteins, peptides or amino acids involving lipoproteins G01N33/92
• CPC Class Codes: G01N 33/92 involving lipids, e.g. cholesterol , lipoproteins, or their receptors steroid hormones G01N33/743
• CPC Class Codes: Y10T 436/201666 Carboxylic acid

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 the treatment of an inflammatory skin disease that is mediated by VCAM-1 comprising administering an effective amount to inhibit the expression of VCAM-1 of the dithiocarbamate of the formula A-SC(S)-B

wherein A is selected from the group consisting of hydrogen, a pharmaceutically acceptable cation, and a physiologically cleavable leaving group;

and B is selected from the group consisting of alkyl, alkenyl, alkynyl, alkaryl, aralkyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, alkaryl, heterocyclic, alkylheterocyclic, C_1-6 alkoxy-C_1-10 alkyl, C_1-6 alkylthio-C_1-10 alkyl, NR² R³, --(CHOH)_n CH₂ OH, wherein n is 0, 1, 2, 3, 4, 5, or 6, --(CH₂)_n CO₂ R¹, including alkylacetyl, alkylpropionyl, and alkylbutyryl, and hydroxy (C_1-6)alkyl--, wherein R¹ is hydrogen or a pharmaceutically acceptable cation, and R² and R³ are independently isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, or cyclohexyl, --(CHOH)n(CH2)OH, wherein n is 0, 1, 2, 3, 4, 5, or 6, or R² and R³ together constitute a bridge.

4. The method of claim 1 or 2, wherein A is hydrogen or a pharmaceutically acceptable cation selected from the group consisting of sodium, potassium, calcium, magnesium, aluminum, zinc, bismuth, barium, copper, cobalt, nickel, or cadmium.

5. The method of claim 1 or 2, wherein A is a physiologically cleavable leaving group.

6. The method of claim 1 or 2, wherein A is an acyl group.

7. The method of claim 1 or 2, wherein B is NR² R³, wherein R² and R³ together constitute a bridge of the formula --(CH₂)_m --, wherein m is 3, 4, 5, or 6.

8. The method of claim 1 or 2, wherein B is a heterocyclic or alkylheterocyclic group.

9. The method of claim 1 or 2, wherein the heterocycle is partially or totally hydrogenated.

2. A method for the treatment of a human endothelial cell disorder that is mediated by VCAM-1 comprising administering an effective amount to inhibit the expression of VCAM-1 of the dithiocarbamate of the formula A-SC(S)-B

wherein A is selected from the group consisting of hydrogen, a pharmaceutically acceptable cation, and a physiologically cleavable leaving group;

and B is selected from the group consisting of alkyl, alkenyl, alkynyl, alkaryl, aralkyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, alkaryl, heterocyclic, alkylheterocyclic, C_1-6 alkoxy-C_1-10 alkyl, C_1-6 alkylthio-C_1-10 alkyl, NR² R³, --(CHOH)_n CH₂ OH, wherein n is 0, 1, 2, 3, 4, 5, or 6, --(CH₂)_n CO₂ R¹, including alkylacetyl, alkylpropionyl, and alkylbutyryl, and hydroxy (C_1-6) alkyl--, wherein R¹ is hydrogen or a pharmaceutically acceptable cation, and R² and R³ are independently isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, or cyclohexyl, --(CHOH)n(CH2)OH, wherein n is 0, 1, 2, 3, 4, 5, or 6, or R² and R³ together constitute a bridge.

3. The method of claim 2, wherein the disorder is selected from the group consisting of asthma, psoriasis, eczematous dermatitis, Kaposi'"'"'s sarcoma, multiple sclerosis, and proliferative disorders of smooth muscle cells.

10. The method of claim 2, wherein the dithiocarbamate is B-C(S)S-- is pyrrolidine-N-carbodithioate.