Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1995-06-06
2001-09-11
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S310100
Reexamination Certificate
active
06288100
ABSTRACT:
BACKGROUND OF INVENTION
Proliferation and directed migration of vascular smooth muscle cells are important vascular occlusive components in such processes as hypertension-induced vascular remodeling, vascular restenosis, and atherosclerosis (Gibbons, G. H.; Dzau, V. J.; NEJM, 1994; 330: 1431). The overall disease process is referred to as hyperproliferative vascular disease based on the etiology of the disease process. Vascular occlusion is preceded by stenosis resulting from intimal smooth muscle cell hyperplasia (Clowes, A. W.; Reidy, M. A.; J. Vasc. Surg., 1991, 13: 885). The underlying cause of intimal smooth muscle cell hyperplasia is vascular smooth muscle cell injury leading to disruption of the endothelium and extracellular matrix (Schwartz, S. M., Human Pathology, 1987; 18: 240; Fingerle, J., Arteriosclerosis, 1990; 10: 1082). Normally, the cells of the arterial wall are under close negative control and in a low basal proliferating state or in a quiescent non-proliferating state. Following vascular injury, the release of growth factors and cytokines result in smooth muscle cell proliferation and migration (Fagin, J. A.; Forrester, J. S., Trends in Cardiovascular Med., 1992; 2; 90.; Shiratani, M.; Yui, Y.; Kawai, C., Endothelium, 1993; 1: 5).
Vascular injury leading to intimal hyperplasia can be induced immunologically or by invasive cardiovascular procedures. Atherosclerosis is a common form of biologically mediated vascular injury progressing to stenosis. Abnormal proliferation of vascular smooth muscle cells is a feature of atherosclerotic plaques responsible for obstructive neo-intimal lesions at the site of intimal damage (Ross, R., Nature, 1993: 362; 801; Cascells, W., Circulation, 1992; 86: 723). Mechanical injury leading to intimal hyperplasia can occur following angioplasty procedures, organ transplant surgery and other vascular invasive procedures that disrupt vascular integrity (Clowes, A. W.; Reidy, M. A., J. Vasc. Surg., 1991; 13: 885; Isik, F. F.; McDonald, T. O.; Ferguson, M.; Yanaka, E., Am. J. Pathol., 1992; 141: 1139).
Percutaneous transluminal coronary angioplasty has achieved wide acceptance for the treatment of coronary artery stenosis. In this procedure the endothelium is damaged and exposed to a variety of chemoattractants and mitogens which are either blood-borne or are released at the site of injury. Among these agents, platelet-derived growth factor (PDGF) is thought to play a significant role in the process of smooth muscle cell proliferation and chemotaxis (Reidy, M. A.; Fingerle, J.; Lindner, V.; Circulation, 1993: 86 (suppl III): III-43.; Ferns, G. A. A.; Raines, E. W.; Sprugel, K. H.; Montani, A. S.; Reidy, M. A.; Ross, R.; Science, 1991; 253: 1129.; Jawien, A., et al., J. Clin. Invest., 1992; 89: 507; Nabel, E. G., et al., J. Clin. Invest., 1993; 91: 1822). Within 3 to 6 months after angioplasty, a significant reduction in blood flow occurs in approximately 30-40% of patients as a result of restenosis caused by response to vascular injury during this procedure. These patients then require a second interventional procedure (Pepine, C., Circulation, 1990; 81: 1753.; Hardoff, R. J., J. Am. Coll. Cardiol., 1990; 15: 1486). Accordingly, agents that limit the restenosis process are of significant benefit. Agents that inhibit vascular smooth muscle cell proliferation, particularly PDGF-stimulated proliferation, are useful in the treatment of vascular hyperproliferative disorders (Molloy, C. J., Drug Dev. Res., 1993; 29: 148.; Newby, A. C.; George, S. J., Cardiovasc. Res., 1993; 27: 1173).
DE 4, 129, 603 discloses fused heterocyclic compounds (benzimidazoles) as inhibitors of collagen-induced platelet aggregation and fibrinogen, that may also be useful in the “treatment of transluminal angioplasty”. U.S. Pat. No. 5,387,600 discloses 2-thio substituted benzimidazoles for the treatment of atherosclerosis. U.S. Pat. No. 5,026,705 discloses 2-styryl benzimidazolyl pyridazinones as positive inotropic agents useful in the treatment of congestive heart failure.
U.S. Pat. No. 5,200,422 discloses a family of 1-(substituted phenyl or naphthyl)-2H -benzimidazole-2-ones as potassium channel openers. U.S. Pat. No. 4,814,329 discloses 5-substituted-2-thiono or substituted-thio benzimidazole derivatives for treatment of hyperlipoproteinemic diseases and inhibition of atherosclerosis and thrombus formation. U.S. Pat. No. 5,376,665 discloses a group of 4-(benzimidazol -2-yl and benzthiazol -2-yl)-carbamoyl or sulfamoyl-benzyl phosphonate derivatives for the treatment of diabetes and hyperlipidemia.
DESCRIPTION OF THE INVENTION
In accordance with this invention, there is provided a group of benzoyl benzimidazoles (formula I) and reduction products thereof (formula II) as well as pharmaceutical compositions containing those compounds and the method of using the compounds in the treatment of conditions involving excessive smooth muscle cell proliferation such as restenosis, as follows:
wherein R is alkyl of 1 to 6 carbon atoms, phenyl or phenyl substituted with halogen, hydroxyl, alkoxy of 1 to 6 carbon atoms, trifluoromethyl or alkyl of 1 to 6 carbon atoms; R
2
is hydrogen, halogen, alkoxy of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms; R
1
is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, arylalkyl of 7 to 12 carbon atoms, or benzyl substituted with halogen, carboxyl, alkoxycarbonyl of 2 to 6 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms, or a pharmaceutically acceptable salt thereof.
The compounds of this invention are prepared according to the general sequence of reactions outlined in the following scheme:
The iminoether hydrochloride (1) is prepared by reacting an appropriate nitrile with an alcohol and hydrogen chloride at around 0° C. Reaction of (1) and a 3,4-diaminobenzophenone in refluxing ethanol affords the corresponding benzoyl benzimidazole (2) substituted in the 2-position. Alkylation of (2) with an alkyl, aryl or arylalkyl halide in dimethyl formamide using sodium hydride as base affords the regioisomers (3a, 3b). The isomers can be separated by recrystallization and chromatography. The benzoylbenzimidazoles further can be reduced with sodium borohydride in ethanol to obtain the corresponding alcohols (4a, 4b).
The pharmaceutically acceptable acid addition salts are those derived from such organic and inorganic acids as: acetic, lactic, citric, fumaric, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, methylbenzene sulfonic, and similarly known acceptable acids. With those compounds possessing an acidic substituent such as the carboxylic acids, the pharmaceutically acceptable salts include the alkali metal salts (sodium or potassium), the alkaline earth metal salts (calcium or magnesium) and ammonium salts.
This invention includes pharmaceutical compositions comprised of the benzimidazoles of the invention either alone or in combination with excipients (i.e. pharmaceutically acceptable materials with no pharmacological effect). Such compositions are useful in treating diseases which are characterized by excessive smooth muscle cell proliferation most frequently arising from vascular reconstructive surgery and transplantation, for example, balloon angioplasty, vascular graft surgery, coronary artery bypass surgery, and heart transplantation. Other disease states in which there is unwanted vascular proliferation include hypertension, asthma, and congestive heart failure. The compounds of this invention are thus useful for treating these diseases and states.
The compounds of this invention may be administered systemically, for example by intravenous injection, typically ranging from 0.1 to 10 mg/kg/h over 5-30 days, by subcutaneous injection at lower dose or by oral administration at higher dose than intravenous injection. Localized delivery of the compounds of this invention may also be achieved by transmembrane, transdermal or other topical administrative routes using appropriate continuous release devices such as a supporting matrix, where app
Chai Sie-Yearl
Elokdah Hassan M.
Sulkowski Theodore S.
American Home Products Corporation
Eck Steven R.
Morris Patricia L.
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