METHOD OF TREATING ABNORMAL TISSUE PROLIFERATION BY ADMINISTERING AN ANGIOTENSIN II ANTAGONIST

Abstract: The present invention is directed to a method of treating restenosis, atherosclerosis or neointimal hyperplasia of vascular smooth muscle in a patient by administering known compounds which are useful as inhibitors of the Angiotensin II AT-2 receptor subtype.

Description: METHOD OF TREATING ABNORMAL TISSUE PROLIFERATION BY ADMINISTERING AN ANGIOTENSIN II ANTAGONIST Cross-ReferenceTo Related Application This application is a continuation-in-part of U.S. application Serial No. 07/837,446 filed February 14, 1992. Technical Field The present invention relates to a method of treating a patient having restenosis or atherosclerosis, both of which involve the occlusion of arterial vessels by vascular smooth muscle cells, said treatment being achieved by administering pharmaceutically useful compounds which are angiotensin II receptor antagonists. The invention is also with reducing neointimal hyperpla¬ sia of vascular smooth muscle. Backgro nd Art Atherosclerotic arterial occlusive disease is a major cause of morbidity and mortality in the United States (W.P. Castelli, AM J. MED., 76:4-12 (1984)). One important strategy in the treatment of this disorder is the use of various revascularization techniques such as saphenous vein bypass grafting, endarterectomy, and transluminal coronary angioplasty. Unfortunately, the overall success of these revascularization procedures is limited by restenosis due to neointimal hyperplasia. The magnitude of this problem in clinical medicine is increasing with the rising rate of cardiovascular surgery and interventional therapy. Several factors have been implicated in the pathogenesis of restenosis, including the hormone angiotensin II (Ang II) , which is an integral part of the renin-angiotensin system and is a regulator of vascular tone and structure. Ang II is a potent vaso¬ constrictor which plays a central role in hypertension, congestive heart failure, and vascular diseases. In vivo, Ang II is implicated in the vascular hypertrophy of hypertension since angiotensin converting enzyme (ACE) inhibitors can prevent or attenuate medial hyper¬ trophy in many models of hypertension (G.K. Owens, CIRC. RES., 56:525-536 (1985)). Recently it has been found that inhibitors of ACE will reduce or attenuate the development of intimal hyperplasia in the rat in re¬ sponse to injury (J.S. Powell et al., SCIENCE, 245:186- 188 (1989)). These growth inhibitory effects are independent of the hemodynamic effects of ACE inhibitors since treatment with other blood pressure lowering drugs does not inhibit this growth (J.S. Powell et al., J. CARD. PHARMACOL. 16 (Suppl. 4):S42-S49 (1990)). Similar studies have shown that ACE inhibitors prevent vascular growth in response to injury in guinea pigs (J.P. Clozel et al., "Inhibition Of Converting Enzyme and Neointima Formation After Vascular Injury In Rabbits and Guinea Pigs M , HYPERTENSION 18 [Suppl. II]: 1155-1159, 1991), and arterial and venous allograft-induced vascular injury in rats (D. Plissonnier et al., "Effect of Converting Enzyme Inhibition On Allograft-induced Arterial Wass Injury And Response", HYPERTENSION 18 [Suppl II]: 1147- 1143, 1991; S.P. Roux et al., "Cilazapril Inhibits Wall Thickening of Vein Bypass Graft In The Rat", HYPERTENSION 18 [Suppl II]: 1143-1146, 1991. Moreover, ACE inhibi¬ tors can prevent or attenuate atherosclerosis in Watanabe rabbits (A.V. Chobanian, "The Effects of ACE Inhibitors and Other Hypertensive Drugs On Cardiovascu- lar Risk Factors and Artherogenesis", CLIN. CARDIOL. , 12:43-48, 1990) and cholesterol fed primates (G. Aberg, "Effects of Captopril on Artherosclerosis in Cynomolgus Monkeys", J. CARDIOVASCULAR PHARMACOL., 15 (Suppl 5): S56- S72, 1990). Angiotensin II has also been shown to play a role in the regulation of vascular smooth muscle cell growth in vitro. In cultured vascular smooth muscle cells, Ang II increases the rates of RNA and protein synthesis and under certain conditions is mitogenic. Moreover, Ang II increases the expression of the proto- oncogenes c-myc, c-jun, and c-fos, as well as growth factors which are involved in Ang II-induced growth, namely, platelet derived growth factor (PDGF) , basic fibroblast growth factor, and transforming growth factor-jS (TGF-0) (A.J. Naftilan et al., J. CLIN. INVEST., 83:1419-1424 (1989); A.J. Naftilan et al. , HYPERTENSION, 13:706-711 (1989); G.H. Gibbons et al. , HYPERTENSION, 14:358 (1989)). The results from multiple laboratories suggest the existence of receptor isoforms which possess differ¬ ent binding properties and different intracellular signals. Recently, two classes of receptor antagonists have been used to classify these receptors (A.T. Chiu et al., BIOCHEM. BIOPHYS. RES. COMM. , 165:196-203 (1989)). The AT-1 receptors, present on multiple cell types, appear to be coupled via G proteins to phospholipase C. AT-1 receptors are known to be selectively antagonized by Dup753 (A.T. Chiu et al., BIOCHEM. BIOPHYS. RES. COMM. , 172:1195-1202 (1990); D.T. Dudley et al. , MOL. PHARMACOL., 38:370-377 (1990)). Stimulation of this receptor leads to inositol metabolism, increases in intracellular calcium, and activation of protein kinase c. Thus, the AT-1 receptor is the classical membrane Ang II receptor. Blockade of these receptors have been shown to inhibit injury induced vascular growth (W. Oεterrieder et al., "Role of Angiotensin II in Injury-Induced Neointi a Formation in Rats", HYPERTENSION 18, [Suppl II]: 11-60- 1164, 1991; H. Azuma et al., Prevention of Intimal Thickening After Endothelial Removal By A Nonpeptide Angiotensin II Antagonist, MK-965", BR. J. PHARMACOL, 1991; and S. Laporte et al., Angiotensin II Antagonists Prevent the Myoproliferative Response after Vascular Injury, THE FASEB JOURNAL 5, No. 4, I-A869, 1991. A second Ang II receptor subtype, AT-2, has already been recently discovered and this receptor has a more limited distribution and is not coupled to G proteins. This receptor has been found to bind selec¬ tively to compounds utilized in the present invention and in particular to (S)-l-[ [4-(dimethylamino)-3-methyl- phenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-lH- imidazo[4,5]pyridine-6-carboxylic acid (Formula II). Currently, the physiologic role of this receptor is unknown, but it has been speculated that this receptor may mediate the growth potentiation effects of Ang II. This is based on the observation that this receptor subtype is expressed during fetal development (E.F. Grady et al., J. CLIN. INVEST., 88:921-933 (1991); K. Tsutsumi et al. , AM. J. PHYSIOL. 261:H667-H670 (1991); Viswanathan et al. , BIOCHEM. BIOPHYS. RES, COMM., 170:1361- 1367 (1991)) reported that AT-2 receptors are the predominant isoform in the neonatal vasculature but are only a minor component in that of the adult. The mechanism of action of the compounds utilized in the present invention may be via their binding of the AT-2 receptor. Summary OfThe Invention One embodiment of the present invention is to provide a method for preventing or reducing neointimal hyperplasia of vascular smooth muscle cells in a patient in need thereof which comprises administering an effec¬ tive amount of a compound of Formula I or a pharmaceuti¬ cally acceptable salt thereof to the patient. Another embodiment of the present invention is a method for preventing, limiting or slowing the pro- gression of post-surgical vascular restenosis in a patient in need thereof which comprises administering to said patient an effective amount of the compound of Formula I. Another embodiment of the present invention is to provide a method for preventing or alleviating atherosclerosis in a patient in need thereof which comprises administering to said patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. Another embodiment of the present invention concerns a method for preventing, limiting or slowing the progression of post-surgical vascular restenosis in a patient in need thereof which comprises co-administra¬ tion of an effective amount of a compound of Formula I with an effective amount of a lipid modulating, anti- hypertensive, anti-anginal, anti-coagulant or thrombolic drug to said patient. Another embodiment aspect of the present invention concerns a method for preventing or alleviat¬ ing atherosclerosis in a patient in need thereof which comprises co-administration of an effective amount of the compound of Formula I and an effective amount of a lipid modulating and/or anti-hypertensive drug. The compounds of Formula I used in practicing the present invention are set forth in the formula chart provided hereinafter. BriefDescription OfTheDrawings FIGURE 1 is a plot of the inhibition of the development of neointi a comparing a control with the compound of Formula II; and FIGURE 2 is a plot of specific 3 H Ang II binding v. concentration of AT-1 and AT-2 materials. De ailed Description Of The Inyeption Atherosclerosis is defined as the narrowing of a vessel due to the abnormal growth of vascular smooth muscle cells. The textbook definition of restenosis is recurrent stenosis, after surgical correction of the primary condition with stenosis being the narrowing or stricture of a duct or canal. As used herein, restenosis is taken to mean the narrowing or stricture of an arterial vessel due to proliferation of neointimal vascular smooth muscle cells into the lumen of said vessel. Restenosis as used herein occurs in patients who have been subjected to various arterial interventional procedures including, but not limited to, angioplasty, atheroectomy, endarter¬ ectomy, stint implantation, arterial laser treatment, graft stenosis, such as that seen in coronary artery bypass graft (CABG) , and cardiac transplantation. In essence, restenosis is taken to mean the narrowing or stricture of an arterial vessel due to proliferation of neointimal cells in said vessel resulting from any condition or interventional procedure which disrupts the intimal lining of said vessel. Proliferation of neo¬ intimal cells means the proliferation of arterial undifferentiated vascular smooth muscle cells in the intima of the vessel after the endothelial lining of the vessel has been disrupted. The proliferation of neo- intimal cells can also be referred to as hyperplasia of neointimal cells. Once the endothelium is disrupted, the undifferentiated vascular smooth muscle cells migrate into the lumen and proliferate markedly, thus, ultimately reducing the size of the lumen. This occlu- sion of the lumen of vessels is known to occur within 2 to 6 months following surgical intervention in 30% to 50% of all patients. Heretofore, the only treatment available to such patients has been repetition of the surgical intervention. Atherosclerosis occurs in varying degrees in a vast majority of the population. Similar to resten¬ osis, atherosclerosis is thought to result -from damage to the endothelium which results in the migration of smooth muscle cells into the lumen and the subsequent proliferation. The atherosclerotic lesion also consists of lipid-laden macrophages and fibroblasts. Current drug therapy aims at treating blood lipid abnormalities. There is no available drug therapy that is directed at inhibiting the process of vascular proliferation of atherosclerosis. Advanced atherosclerosis lesions are only treated by surgery intervention with the inherent risk of endothelial damage stated above. It has been found that compounds of Formula I or II (see formula chart hereinafter) or pharmaceutical¬ ly acceptable salts thereof are useful in preventing or alleviating the neointimal hyperplasia, thus rendering them useful in treating restenosis in a patient. The term "treating restenosis" means providing any reduction in or the prevention of restenosis. The compounds employed in the present inven¬ tion are known to bind the Ang II AT-2 receptor subtype. It is believed that the ability of the compounds of Formula I to bind the AT-2 receptor plays a role in the utility of the compounds in treating restenosis. The compounds of Formula I are described and claimed in U.S. Patent No. 4,812,462, which issued March 14, 1989. U.S. 4,812,462 is hereby incorporated herein by reference thereto. The compounds of general Formula I and pharmaceutically acceptable salts thereof are described in U.S. 4,812,462 beginning at column 1, line 56 through column 4, line 48. The DETAILED DESCRIPTION OF THE INVENTION section of U.S. 4,812,462 describes the method of synthesis of the compounds of Formula I (column 10, line 5 through column 17, line 27) and the manner of formulating the compounds, the route of administration, and the dosage amount. In practicing the present invention one would use the same dosage amounts, routes of administration, and types of pharma- ceutical composition as are described in U.S. 4,812,462 (see column 20, line 7 through column 22, line 27). Typically, in practicing the present invention a patient would receive an effective amount of a compound of Formula I administered prior to the patient undergoing surgical intervention of their arterial vessels and continue treatment until it is determined, for example, by using angiographic techniques, that treatment is no longer necessary. The utility of the compounds utilized in the present invention in treating restenosis was demonstrat¬ ed in a rat model of carotid artery balloon angioplasty as follows: Eight male Sprague-Dawley rats (400-450 g) were implanted intraperitoneally with Alzet osmotic minipumps (Alza, Inc., Palo Alto, CA) containing (S)-l- [[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenyl- acety1)-4,5,6,7-tetrahydro-lH-imidazo[4,5]pyridine-6- carboxylic acid (see Formula II of Formula Chart provid¬ ed hereinafter) referred to hereafter as the test compound in a 1:1 v/v mixture of 0.9% normal saline and polyethylene glycol 400. The pumps delivered a continu¬ ous infusion of test compound at a total dose of 25 mg/kg/day. A control group was implanted with pumps which contained vehicle alone. After 1 week, the rats were anesthetized and sustained a balloon injury to the left carotid artery, according to the procedure of A.W. Cloves et al., LAB. INVEST., 49:208-215 (1983). Two weeks after this injury, the animals were killed and the left and right carotid arteries were removed for analysis. Adminiεtration of test compound or vehicle alone contin¬ ued during these 2 weeks. The animals were then anes¬ thetized and the carotid artery sections fixed in para- formaldehyde. A Miller's elastin stain was used to delineate the internal and external elastic laminae for an accurate measurement of the medial and neointimal area. The area of the media and neointima was measured using planar morpho etry on a digitizing tablet. Confirmation that the animals actually received the injury was provided by noting the absence of endothelium on hematoxylin and eosin stained sections. In this rat model, the endothelium regenerates from the proximal and distal portions of the carotid but does not extend to the middle third at 2 weeks after the injury (A.W. Clowes et al. f LAB. INVEST., 49:208-215 (1983)). Results for the above experiment (Figure 1) show that the test compound was effective in inhibiting the development of the neointima. We also investigated the distribution of receptor subtypes in the vessel wall following balloon injury. Male Sprague-Dawley rats sustained balloon injury to the left common carotid artery, and were sacrificed in 2 weeks. After sacrifice the carotids were removed, the middle third embedded in optimal cutting temperature medium, and frozen in liquid nitro¬ gen. Sequential 6 μ sections were cut, dried under reduced pressure for 24 hours, and then frozen at -70"C until the radioreceptor binding assay was performed. The sections were brought to room temperature under reduced pressure, and preincubated in a humidified chamber in 10 mmol sodium phosphate buffer containing 150 mmol NaCl, 5 mmol Na 2 EDTA, 0.3 mmol bacitracin, and 0.2% bovine serum albumin. Using an in situ receptor binding assay on frozen carotid artery sections, bound 123 I-[Sar l , He 8 ]-Ang II was visualized by emulsion autoradiograph (F.A.O. Mendelsohn et al., PROC. NATL. ACAD. Sci., 81:1575-1579 (1984); E.F. Grady et al., J. CLIN. INVEST., 88:921-933 (1991)). Results from this experi¬ ment are shown in Figure 2. Binding of Ang II was detected in both the media and the neointima, and this binding was competitive with unlabeled Ang II. The Ang II receptors were not seen in the adventitia. Two weeks after balloon injury, approximately 30% of receptors in the neointima are of the Ang II AT-2 subtype, as shown by the marked reduction in binding achieved with the above test compound. The above data illustrates the utility of the compounds of Formula I in preventing neointimal hyper¬ plasia, thus rendering them useful in the treatment of restenosis. The above data also suggests that the Ang II AT-2 receptor subtype plays a signi icant role in the formation of neointimal hyperplasia. Since atheroscle¬ rosis involves a similar abnormal growth of vascular smooth muscle cells, the data suggest the utility of the compounds of Formula I in preventing or alleviating this condition. The following drugs are examples of agents that might be used in combination with the AT 2 antago¬ nists: Lipid Modulating Drugs lovastatin Lopid (Trademark of Warner-Lambert Company for gemfibrozil) Antihypβrtensive Drugs captopril verapamil enalapril prazosin lysinopril minoxidil quinapril hydralazine cilazapril sodium nitroprusside nifedepine clonidine diltiazem methyldopa Antianginal erythrityl tetranitrate isosorbide dinitrate nitroglycerin Anticoagulant heparin Thrombolvtic urokinase streptokinase tissue plasminogen activator (TPA) Formula Chart FORMULA I wherein (l) R, is selected from the group consisting of: (a) alkyl of from four to twenty carbons, inclu¬ sive, and wherein y is zero, one, two, three, four, or five, R' is cycloalkyl of from four to twenty carbons, inclusive in a one-, two-, or three-saturated ring system, said ring consisting of from four to eight carbons inclusive, each ring unsubstituted or substituted by a straight or branched lower alkyl group; naphthyl; heteroaryl consisting of 2-, 3-, or 4-pyridyl; 1-, 2-, or 4-imidazolyl; 1-, 2-, 3-, 4-, 5-, 6-, or 7-indolyl; 2-, or 3-thienyl; 2-, or 3-furyl; or 1-, 2-, or 3-pyrazolyl, phenyl unsub¬ stituted or substituted with of from one through five substituents selected from the group consist¬ ing of lower alkyl, halo, trifluoromethyl, hydroxy, lower alkoxy, lower alkyl acyloxy, amino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, nitro, and wherein R 10 is lower alkyl, phenyl unsubstituted or substituted by lower alkyl, or -NHR π wherein R n is hydrogen, lower alkyl, cycloalkyl of from four to twenty carbons, inclusive in a one-, two-, or three-saturated ring system, said ring consisting of from four to eight carbons inclusive, each ring unsubstituted or substituted by a straight or branched lower alkyl group; naphthyl; phenyl unsubstituted or substituted with of from one through five substituents selected from the group consisting of alkyl, halo, trifluoromethyl, amino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, and nitro, R" is hydrogen, lower alkyl, cycloalkyl, naphthyl, phenyl unsubstituted or substituted with of from one through five substituents selected from the group consisting of lower alkyl, halo, trifluoro¬ methyl, amino, N-lower monoalkylamino, N, -lower dialkyl amino, lower thioalkyl, lower alkyl sulfo- nyl, and nitro; (2) R j is selected from the group consisting of: (a) hydrogen, (b) halo, (c) lower alkyl, (d) R , -(CH 2 ) I where x is one, two, three, four, or five and R' is independently as defined above, (e) 0 II R'-C- wherein R' is independently as defined above, and (f) R'-CH(OH)- wherein R 1 is independently as defined above; (3) R j is selected from the group consisting of: (a) R'-(-CH 2 -) x wherein x and R' are independently as defined above, (b) R' - CH - R « ' • (CH ), wherein R' and y are independently as defined above, and R' » • is lower alkyl, cycloalkyl of from four to twenty carbons, inclusive in a one-, two-, or three-saturated ring system, said ring consist- 5 ing of from four to eight carbons inclusive, each ring unsubstituted or substituted by a straight or branched lower alkyl group; naphthyl; phenyl unsub¬ stituted or substituted with of from one to five substituents selected from the group consisting of 10 alkyl, halo, trifluoromethyl, amino, N-lower monoalkylamino, N-N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, and nitro; (c) o 15 -C-R, wherein R 5 is selected from the group consisting of: (i) alkyl of from one to fifteen carbons, inclusive, 20 (ii) 25 wherein R' , R", and y are independently as defined above, (iii) -CH=C(R 6 )R, wherein R* is hydrogen or lower alkyl and R, is as defined above, (iv) wherein y, R• , and R are independently as defined above, (v) R'-(-CH 2 -) y -0- wherein y and R' are inde¬ pendently as defined above, and (vi) wherein R' , R", and y are independently as defined above, and (d) 0 II -S-R. II 0 wherein R 5 is independently as defined above; (4) R< is independently selected from the group consist- ing of: (a) -CT^OR, wherein R 7 is independently selected from the group consisting of hydrogen, lower acyl, and lower alkyl, (b) R 7 - N - Rg CH j wherein R 7 is independently as defined above and « is independently selected from the group consisting of hydrogen, lower alkyl, and benzyl, (c) 0 II -CH, (d) -C---N, and (e) -C-OR, wherein R-, is independently selected from the group consisting of hydrogen, lower alkyl, and benzyl; and "lower" as used anywhere above means from one to four carbon atoms. FORMULA II Preferred compounds are as follows: (S)-l-[[4-(dimethylamino)~ 3-methylphenyl]methyl]-5-(diphenylacetyl)- 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]-pyridine-6- carboxylic acid; methyl (S)-l-[ [4-(dimethylamino)- 3-methylphenyl]methyl]-5-(diphenylacetyl)- 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]-pyridine-6- carboxylate; (S)-l-[ (4-amino-3-methylphenyl)methyl]- 5-(diphenylacetyl)-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine-6-carboxylic acid; methyl (S)-l-[ (4-amino-3-methylphenyl)methyl]- 5-(diphenylacetyl)-4,5,6,7-tetrahydro-lH- imidazo[ ,5-c]pyridine-6-carboxylate; (S)-5-(diphenylacetyl) -l-[ [4-(methylamino) -3- methylphenyl]methyl]-4,5,6 , 7-tetrahydro- lH-imidazo[4,5-c]pyridine-6-carboxylie acid; methyl (S)-5-(diphenylacetyl)-l-[ [4-(methylamino)- 3-methylpheny1]methyl]-4 ,5,6,7-tetrahydro- lH-imidazo[4,5-c]pyridine-6-carboxylate; (S)-5-(diphenylacetyl)-l-[ (4-methoxy-3-methyl- pheny1)methyl]-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyri- dine-6-carboxylic acid; methyl (S)-5-(diphenylacetyl)-1-[ (4-methoxy-3- methyl-phenyl)methyl]- 4,5,6,7-tetrahydro-lH-imidazo- [4,5-c]pyridine-6-carboxylate; (S)-5-[bis(4-fluorophenyl)acetyl]-l- [ [4-(dimethylamino)-3-methyl-phenyl]methyl]- 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-6- carboxylic acid; methyl (S)-5-[bis(4-fluorophenyl}acetyl]-l- [ [4-(dimethylamino)-3-methy1-phenyl]methyl]- 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-6- carboxylate; (S)-5-(diphenylacetyl)-l-[(3-methy1-4-nitrophenyl)- methyl]-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine- 6-carboxylic acid; methyl (S)-5-(diphenylacetyl)-l-[ (3-methyl-4- nitrophenyl)-methyl]- 4,5,6,7-tetrahydro-lH-imidazo[4,5- c]pyridine-6-carboxylate; (S)-5-(diphenylacetyl)-l-(phenylmethyl)-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine-6-carboxylic acid; methyl (S)-5-(diphenylacetyl)-1-(phenylmethyl)- 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-6-carboxyl- ate; (S)-[[4-(acetylamino)-3- ethylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7- tetrahydro-lH-imidazo-[4,5-c]pyridine-6- carboxylie acid; methyl (S)-[[4-(acetylamino)-3- ethylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7- tetrahydro-lH-imidazo-[4,5-c]pyridine-6- carboxylate; (S)-5-(diphenylacetyl)-l-[ (4-hydroxy-3- iodo-5-methylphenyl)methyl]-4,5,6,7-tetrahydro- 1H-imidazo[4,5-c]pyridine-6-carboxylic acid; methyl (S)-5-(diphenylacetyl)-l-[ (4-hydroxy-3- iodo-5-methylphenyl}methyl]-4,5,6,7-tetrahydro- lH-imidazo[ ,5-c] yridine-6-carboxylate; (S)-5-(diphenylacetyl)-l-[ (4-hydroxy-3- methylphenyl)methyl]-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine-6-carboxylic acid; methyl (S)-5-(diphenylacetyl)-l-[ (4-hydroxy-3- methylphenyl)methyl]-4,5,6,7-tetrahydro-lH- imidazo[ ,5-c]pyridine-6-carboxylate; (S)-l-[ (4-aminophenyl)-methyl]-5- (diphenylacetyl)-4,5,6,7-tetrahydro-lH-i idazo- [4,5-c]pyridine-6-carboxylic acid; methyl (S)-l-[ (4-aminophenyl)-methyl]-5- (diphenylacetyl)-4,5,6,7-tetrahydro-lH-imidazo- [4,5-c]pyridine-6-carboxylate; (S)-5-(diphenylacetyl)-4,5,6,7- tetrahydro-1-[[4-(trifluoromethyl)- phenyl]methy1-lH-imidazo[4,5-c]pyridine-6- carboxylic acid; methyl (S)-5-(diphenylacetyl)-4,5,6,7- tetrahydro-1-[[4-(trifluoromethyl)- phenyl]methyl]-lH-imidazo[4,5-c]pyridine-6- carboxylate; (S)-5-(diphenylacetyl)-l-[ (3-methylphenyl)methyl]- 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-6-carboxyl- ic acid; methyl (S)-5-(diphenylacetyl)-l-[ (3-methylphenyl)- methyl]- 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-6- carboxylate; (S) -l-(2-(l-adamantyl)ethyl)-5-diphenylacetyl- 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-6-carboxyl- ic acid; methyl (S)-1-(2-(1-adamantyl)ethyl)-5- diphenylacetyl-4,5,6,7-tetrahydro-lH-imidazo[ ,5-c] pyridine-6-carboxylate; 5-(cyclopentylphenylacetyl)-1-[ (4-methoxy-3-methyl- pheny1)methyl]-4 ,5,6,7-tetrahydro-lH-imidazo [4,5- c]pyridine-6-carboxylic acid; methyl 5-(cyclopentylphenylacetyl)-1-[(4-methoxy-3- ethylphenyl)methyl]- ,5,6,7-tetrahydro-1H-imidazo[4,5- c]pyridine-6-carboxylate; and (S)-6-(hydroxymethyl)-N-meth I-N-pheny1-1-(phenyl¬ methyl)-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-5- carboxamide. While the forms of the invention herein disclosed constitute presently preferred embodiments, many others are possible. It is not intended herein to mention all of the possible equivalent forms or ramifi- cations of the invention. It will be understood that the terms used herein are merely descriptive rather than limiting and that various changes may be made without departing from the spirit or scope of the invention.

Claims: What Is Claimed Is: 1. A method for reducing neointimal hyper¬ plasia of vascular smooth muscle in a patient in need thereof which comprises administering to the patient an effective amount of a compound of Formula I (see formula chart) or a pharmaceutically acceptable salt thereof. 2. A method for preventing, limiting or slowing the progression of post-surgical vascular restenosis in a patient in need thereof which comprises administering to the patient an effective amount of a compound of Formula I (see formula chart) or a pharma¬ ceutically acceptable salt thereof. 3. A method for preventing or alleviating the progression of atherosclerosis in a patient in need thereof which comprises administering to the patient an effective amount of a compound of Formula I (see formula chart) or a pharmaceutically acceptable salt thereof. 4. A method for preventing, limiting or slowing the progression of post-surgical vascular restenosis in a patient in need thereof which comprises co-administrating an effective amount of a compound of Formula I (see formula chart) plus an effective amount of a lipid modulating, antihypertensive, antianginal, anticoagulant or thrombolytic drugs to the patient or a pharmaceutically acceptable salt thereof. 5. A method according to claim 3 which further comprises co-administrating to the patient an effective amount of a compound of Formula I plus an effective amount of a lipid modulating and/or antihy- pertensive drug or a pharmaceutically acceptable salt thereof. 6. The method of claims l, 2, 3, 4 or 5 wherein the compound of Formula I contains: (1) R, is attached to N j and is R' - CH - R" I (CH*), wherein y is zero, R" is hydrogen, R' is phenyl unsubstituted or substituted with from one through five substituents selected from the group consisting of lower alkyl, halo, trifluoro- methyl, hydroxy, lower alkoxy, amino, N-lower monoalkylamino, N,N-lower dialkylamino, nitro and -NHCR 10 wherein R 10 is lower alkyl, (2) Ε_ is hydrogen. (3) R 3 is - CR 3 - wherein R 3 is (a) wherein y is ze R' and R" are independently phenyl, cycloalkyl of from four to seven carbons or lower alkyl, (b) R' - (CHjJ y - N - R 6 wherein y is zero, R' is phenyl, cycloalkyl of from four to seven carbons or lower alkyl, and R 6 is lower alkyl, (4) R< is 0 -C IIOR* wherei .n R ,* i .s hydrogen, lower alkyl or benzyl. 7. The method of claims 1, 2 , 3 , 4 or 5 wherein the compound of Formula I contains: (1) R, is attached to N, and is R' - CH - R" (CH,), wherein y is zero, R" is hydrogen, R' is phenyl substituted with from one to three substituents selected from the group of lower alkyl, halo, hydroxy, lower alkoxy, amino, N-lower monoalkyl amino, and N,N-lower dialkylamino, (2) R j is hydrogen. (3) R- 3 is -CR 5 wherein R 5 is wherein y is zero, R 1 and R" are both phenyl, (4 ) 4 is 0 -COR 9 wherein R 9 is hydrogen, lower alkyl or benzyl. 8. The method of claims 1, 2, 3, 4 or 5 wherein the compound of Formula I is selected from the group consisting of: (S)-l-[[4-(dimethylamino)-3-methylphenyl]methyl]-5- (diphenylacetyl)-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]- pyridine-6-carboxylic acid; methyl (S)-l-[ [4-(dimethylamino)-3-methylphenyl]- ethyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-lH-imi- dazo[4 ,5-c]-pyridine-6-carboxylate; (S)-l-[ (4-amino-3-methylphenyl)methyl]-5-(diphenyl¬ acetyl)-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-6- carboxylic acid; methyl (S)-l-[ (4-amino-3-methylphenyl)methyl]- 5-(diphenylacetyl)-4,5,6,7-tetrahydro-lH-imidazo[4,5- c]pyridine-6-carboxylate; (S) -5-(diphenylacetyl)-l-[ [4-(methylamino)-3- methylphenyl]methyl]- ,5,6,7-tetrahydro-lH-imidazo[4,5- c]pyridine-6-carboxylic acid; methyl (S)-5-(diphenylacetyl)-l-[[4-(methylamino)- 3-methylphenyl]methyl]-4 , 5,6,7-tetrahydro-lH-imi¬ dazo[4,5-c]pyridine-6-carboxylate; (S)-5-(diphenylacetyl)-l-[(4-methoxy-3-methyl¬ phenyl)methyl]-4,5,6,7-tetrahydro-lH-imidazo[ ,5-c]pyri- dine-6-carboxylic acid; methyl (S)-5-(diphenylacetyl)-l-[ (4-methoxy-3- methyl-phenyl)methyl]- 4,5,6,7-tetrahydro-lH-imidazo- [4 ,5-c]pyridine-6-carboxylate; (S)-5-[bis(4-fluorophenyl)acetyl]-l-[ [4-(dimethyl- amino)-3-methyl-phenyl]methyl]-4,5,6,7-tetrahydro-1H- imidazo[4 ,5-c]pyridine-6-carboxylic acid; methyl (S)-5-[bis(4-fluorophenyl}acetyl]-l-[ [4- (dimethylamino)-3-methyl-phenyl]methyl]-4,5,6,7-tetra¬ hydro-lH-imidazo[4,5-c]pyridine-6-carboxylate; (S)-5-(diphenylacetyl)-l-[(3-methy1-4-nitrophenyl)- methyl]-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine- 6-carboxylic acid; methyl (S)-5-(diphenylacetyl)-l-[ (3-methyl-4- nitrophenyl)-methyl]- 4,5,6,7-tetrahydro-lH-imidazo[4,5- c]pyridine-6-carboxylate; (S)-5-(diphenylacetyl)-l-(phenylmethyl)-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine-6-carboxylic acid; methyl (S)-5-(diphenylacetyl)-1-(phenylmethyl)- 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-6-carboxyl- ate; (S)-[ [4-(acetylamino)-3-methylphenyl]methyl]-5- (diphenylacetyl)-4,5,6,7-tetrahydro-lH-imidazo-[4,5- c]pyridine-6-carboxylic acid; methyl (S)-[ [4-(acetylamino)-3-methylphenyl]- methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-lH-imi- dazo-[4,5-c]pyridine-6-carboxylate; (S) -5-(diphenylacetyl)-l-[ (4-hydroxy-3-iodo-5- methylphenyl)methyl]-4,5,6,7-tetrahydro-lH-imidazo[4,5- c]pyridine-6-carboxylic acid; methyl (S)-5-(diphenylacetyl)-l-[ (4-hydroxy-3- iodo-5-methylphenyl}methyl]-4,5,6 ,7-tetrahydro- lH-imidazo[ ,5-c]pyridine-6-carboxylate; (S)-5-(diphenylacetyl)-l-[ (4-hydroxy-3- methylphenyl)methyl]-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine-6-carboxylie acid; methyl (S)-5-(diphenylacetyl)-l-[ (4-hydroxy-3- ethylphenyl)methyl]-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine-6-carboxylate; (S)-l-[ (4-aminophenyl)-methyl]-5-(diphenylacetyl)- 4,5,6,7-tetrahydro-IH-imidazo-[4,5-c]pyridine-6-carbox- ylic acid; methyl (S)-l-[ (4-aminophenyl)-methyl]-5-(diphenyl- acetyl)-4,5,6,7-tetrahydro-IH-imidazo-[ ,5-c]pyridine-6- carboxylate; (S)-5-(diphenylacetyl)-4,5,6,7-tetrahydro-l-[ [4- (trifluoromethyl)-phenyl]methyl-lH-imidazo[4,5-c]pyri- dine-6-carboxylic acid; methyl (S) -5- (diphenylacetyl) -4,5,6, 7-tetrahydro-l- [ [4- ( trif luoromethyl) -phenyl ] methy l]-lH-imidazo[ , 5- c] pyr idine-6-carboxy late ; (S) -5- (diphenylacetyl) -l-[ ( 3-methy lphenyl) methyl ]- 4,5,6,7 -tetrahydro- IH-imidazo [ 4 , 5-c ] pyridine-6-carboxy 1- ic acid; methyl (S) -5- (diphenylacetyl) -l-[ ( 3 -methy lphenyl) - methyl ] - 4,5,6, 7-tetrahydro-lH-imidazo [ 4 , 5-c] pyridine-6- carboxylate; (S) -l- (2- (l-adamantyl) ethyl) -5-diphenylacetyl- 4,5,6, 7-tetrahydro-lH-imidazo[ 4 , 5-c]pyridine-6-carboxyl- ic acid; methyl (S) -1- (2- (l-adamantyl) ethyl) -5-diphenylacet- yl-4 , 5, 6 , 7-tetrahydro-lH-imidazo[4 , 5-c ] pyridine-6 - carboxylate; 5- (cyclopentylphenylacetyl) -l-[ ( -methoxy-3 -methyl¬ phenyl) methyl ] -4 , 5 , 6 , 7-tetrahydro-lH-imidazo [4,5- c)pyridine-6-carboxylic acid; methyl 5- (cyclopentylphenylacetyl) -1- [ (4-methoxy-3- methylphenyl ) methyl ] -4,5,6,7 -tetrahydro-lH-imidazo [4,5- c] pyr idine-6-carboxy late; and (S) -6-(hydroxymethyl) -N-methyl-N-phenyl-1- (phenyl¬ methyl) -4,5,6, 7-tetrahydro-lH-imidazo [ 4 , 5-c]pyridine-5- carboxamide . 9. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is (S)-l-[[4- (dimethylamino)-3-methylphenyl]methyl]-5-(diphenyl¬ acetyl)-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]-pyridine-6- carboxylic acid. 10. The method of claims l, 2, 3, 4 or 5 wherein the chemical compound of Formula I is methyl (S)-l-[ [4-(dimethylamino)-3-methylphenyl]methyl]-5- (diphenylacetyl)-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]- pyridine-6-carboxylate. 11. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is (S)-l-[(4- amino-3-methylphenyl)methyl]-5-(diphenylacetyl)-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine-6-carboxylic acid. 12. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is methyl (S)-l-[ (4-amino-3-methylphenyl)methyl]-5-(diphenyl- acetyl)-4,5,6,7-tetrahydro-IH-imidazo[4,5-c]pyridine-6- carboxylate. 13. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is (S)-5- (diphenylacetyl)-l-[ [4-(methylamino)-3-methylphenyl]- methyl]-4,5,6,7-tetrahydro-IH-imidazo[ ,5-c]pyridine-6- carboxylic acid. 14. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is methyl (S)-5-(diphenylacetyl)-1-[ [4-(methylamino)-3-methyl- pheny1]methyl]-4,5,6,7-tetrahydro-IH-imidazo[4,5-c]pyri- dine-6-carboxylate. 15. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is (S)-5- (diphenylacetyl)-1-[ ( -methoxy-3-methy1-phenyl)methyl]- 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-6-carboxyl- ic acid. 16. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is methyl (S)-5-(diphenylacetyl)-l-[ (4-methoxy-3-methyl-phenyl)- methyl]-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-6- carboxylate. 17. The method of claims l, 2, 3, 4 or 5 wherein the chemical compound of Formula I is (S)-5- [bis(4-fluorophenyl)acetyl]-1-[ [4-(dimethylamino)-3- methy1-phenyl]methyl]-4,5,6,7-tetrahydro-lH-imidazo[4,5- c]pyridine-6- carboxylic acid. 18. The method of claims l, 2, 3, 4 or 5 wherein the chemical compound of Formula I is methyl (S)-5-[bis(4-fluorophenyl}acetyl]-l-[[4-(dimethylamino)- 3-methy1-phenyl]methyl]-4,5,6,7-tetrahydro-lH-imida- zo[4,5-c]pyridine-6-carboxylate. 19. The method of claims 1, 2 , 3, 4 or 5 wherein the chemical compound of Formula I is (S)-5- (diphenylacetyl)-l-f (3-methyl-4-nitrophenyl)-methyl]- 4,5,6,7-tetrahydro-IH-imidazo[4,5-c]pyridine-6-carbox- ylic acid. 20. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is methyl (S) -5-(diphenylacetyl)-1-[ (3-methyl-4-nitrophenyl)- methyl]-IH-imidazo[4,5-c]pyridine-6-carboxylate. 21. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is (S)-5- (diphenylacetyl)-1-(phenylmethyl)-4,5,6,7-tetrahydro-IH- imidazo[4,5-c]pyridine-6-carboxylie acid. 22. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is methyl (S)-5-(diphenylacetyl)-1-(phenylmethyl)-4,5,6,7-tetra- hydro-IH-imidazo[4,5-c]pyridine-6-carboxylate. 23. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is (S)-[[4- (acetylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)- 4,5,6,7-tetrahydro-IH-imidazo-[4,5-c]pyridine-6- carboxylie acid. 24. The method of claims 1, 2 , 3 , 4 or 5 wherein the chemical compound of Formula I is methyl (S) -[ [4-(acetylamino)-3-methylphenyl]methyl]-5-(di- phenylacety1)-4,5,6,7-tetrahydro-lH-imidazo-[4 ,5-c]pyri- dine-6-carboxylate. 25. The method of claims 1, 2 , 3 , 4 or 5 wherein the chemical compound of Formula I is (S)-5- (diphenylacetyl)-l-[ (4-hydroxy-3-iodo-5-methylphenyl)- methyl]-4,5,6,7-tetrahydro-IH-imidazo[4,5-c]pyridine-6- carboxylic acid. 26. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is methyl (S)-5-(diphenylacetyl)-l-[ (4-hydroxy-3-iodo-5-methyl- pheny1}methy1]- ,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyri- dine-6-carboxylate. 27. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is (S)-5- (diphenylacetyl)-l-[ (4-hydroxy-3-methylphenyl)methyl]- 4,5,6,7-tetrahydro-IH-imidazo[ ,5-c]pyridine-6-carboxyl- ic acid. 28. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is methyl (S)-5-(diphenylacetyl)-l-[ (4-hydroxy-3-methylphenyl)- methyl]-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-6- carboxylate. 29. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is (S)-l-[(4- aminophenyl)-methyl]-5-(diphenylacetyl)-4,5,6,7-tetra- hydro-lH-imidazo-[4,5-c]pyridine-6-earboxylic acid. 30. The method of claims 1, 2 , 3 , 4 or 5 wherein the chemical compound of Formula I is methyl (S)-l-[ (4-aminophenyl) -methyl]-5-(diphenylacetyl) - 4,5,6,7-tetrahydro-lH-imidazo-[4,5-c]pyridine-6-carbox- ylate. 31. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is (S)-5- (diphenylacetyl)-4,5,6,7-tetrahydro-l-[ [4-(trifluoro- methyl) -phenyl]methyl-lH-imidazo[4,5-c]pyridine-6- carboxylic acid. 32. The method of claims l, 2, 3, 4 or 5 wherein the chemical compound of Formula I is methyl (S)-5-(diphenylacetyl)-4,5,6,7-tetrahydro-l-[ [4-(tri- fluoromethyl)-phenyl]methyl]-IH-imidazo[4 ,5-c]pyridine- 6-carboxylate. 33. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is (S)-5- (diphenylacetyl)-1-[ (3-methylphenyl)methyl]-4 ,5,6,7- tetrahydro-IH-imidazo[4,5-c]pyridine-6-carboxylie acid. 34. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is methyl (S)-5-(diphenylacetyl) -l-[ (3-methylphenyl)methyl]- 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine-6-carbox- ylate. 35. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is (S)-l-(2- (l-adamantyl)ethyl)-5-diphenylacetyl-4,5,6,7-tetrahydro- 1H-imidazo[4 ,5-c]pyridine-6-carboxylie acid. 36. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is methyl (S)-1-(2-(l-adamantyl)ethyl)-5-diphenylacetyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridine-6-carboxylate. 37. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is 5-(cyclo¬ pentylphenylacetyl) -1-[ (4-methoxy-3-methylphenyl) - methyl]-4,5,6,7-tetrahydro-lH-imidazo [4,5-c]pyridine-6- carboxylic acid. 38. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is methyl 5- (cyclopentylphenylacetyl) -l-[ (4-methoxy-3-methyl- pheny1)methyl]-4,5,6,7-tetrahydro-IH-imidazo[4,5-c]pyri- dine-6-carboxylate. 39. The method of claims 1, 2, 3, 4 or 5 wherein the chemical compound of Formula I is (S)-6- (hydroxymethyl)-N-methyl-N-phenyl-1-(phenylmethyl)- 4,5,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxa- mide. 40. A composition comprising a compound of Formula I (see formula chart) or a pharmaceutically acceptable salt thereof and an effective amount of a lipid modulating drug. 41. A composition comprising a compound of Formula I (see formula chart) or a pharmaceutically acceptable salt thereof and an effective amount of a antihypertensive drug. 42. A composition comprising a compound of Formula I (see formula chart) or a pharmaceutically acceptable salt thereof and an effective amount of an antianginal drug. 43. A composition comprising a compound of Formula I (see formula chart) or a pharmaceutically acceptable salt thereof and an effective amount of an anticoagulant drug. 44. A composition comprising a compound of Formula I (see formula chart) or a pharmaceutically acceptable salt thereof and an effective amount of a thrombolytic drug. 45. A composition comprising an effective amount of a compound of Formula I (see formula chart) or a pharmaceutically acceptable salt thereof for reducing neointimal hyperplasia of vascular smooth muscle and an effective amount of a lipid modulating drug. 46. A composition comprising an effective amount of a compound of Formula I (see formula chart) or a pharmaceutically acceptable salt thereof for reducing neointimal hyperplasia of vascular smooth muscle and an effective amount of an antihypertensive drug. 47. A composition comprising an effective amount of a compound of Formula I (see formula chart) or a pharmaceutically acceptable salt thereof for reducing neointimal hyperplasia of vascular smooth muscle and an effective amount of an antianginal drug. 48. A composition comprising an effective amount of a compound of Formula I (see formula chart) or a pharmaceutically acceptable salt thereof for reducing neointimal hyperplasia of vascular smooth muscle and an effective amount of an anticoagulant drug. 49. A composition comprising an effective amount of a compound of Formula I (see formula chart) or a pharmaceutically acceptable salt thereof for reducing neointimal hyperplasia of vascular smooth muscle and an effective amount of a thrombolytic drug. 50. A composition comprising an effective amount of a compound of Formula I (see formula chart) or a pharmaceutically acceptable salt thereof for prevent- ing or alleviating the progression of atherosclerosis and an effective amount of a thrombolytie drug.

Inventors: DZAU VICTOR JOSEPH, PRATT RICHARD ELLSWORTH, DZAU, VICTOR, JOSEPH, PRATT, RICHARD, ELLSWORTH
Applicants: WARNER LAMBERT CO, WARNER-LAMBERT COMPANY
Application year: 1993
Main classification: A61K31
IPC codes: A61K31, A61P9, C07D471