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WO1993015734A1 - Procede de traitement de la proliferation de tissus anormaux par l'administration d'antagoniste de l'angiotensine ii - Google Patents

Procede de traitement de la proliferation de tissus anormaux par l'administration d'antagoniste de l'angiotensine ii Download PDF

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Publication number
WO1993015734A1
WO1993015734A1 PCT/US1993/000390 US9300390W WO9315734A1 WO 1993015734 A1 WO1993015734 A1 WO 1993015734A1 US 9300390 W US9300390 W US 9300390W WO 9315734 A1 WO9315734 A1 WO 9315734A1
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WO
WIPO (PCT)
Prior art keywords
methyl
tetrahydro
imidazo
formula
pyridine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1993/000390
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English (en)
Inventor
Victor Joseph Dzau
Richard Ellsworth Pratt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Priority to EP93903529A priority Critical patent/EP0625902A1/fr
Priority to JP5514070A priority patent/JPH07503729A/ja
Publication of WO1993015734A1 publication Critical patent/WO1993015734A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • 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.
  • 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.
  • saphenous vein bypass grafting grafthelial grafting
  • endarterectomy CAD
  • transluminal coronary angioplasty transluminal coronary angioplasty
  • Ang II angiotensin II
  • ACE angiotensin converting enzyme
  • 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.
  • Ang II increases the rates of RNA and protein synthesis and under certain conditions is mitogenic.
  • 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)
  • PDGF platelet derived growth factor
  • TGF-0 transforming growth factor-jS
  • 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. O ⁇ terrieder 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.
  • 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).
  • (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).
  • 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.
  • 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.
  • FIGURE 1 is a plot of the inhibition of the development of neointi a comparing a control with the compound of Formula II;
  • FIGURE 2 is a plot of specific 3 H Ang II binding v. concentration of AT-1 and AT-2 materials.
  • 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.
  • 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.
  • CABG coronary artery bypass graft
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • Admini ⁇ tration 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)).
  • 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) Antihyp ⁇ rtensive Drugs captopril verapamil enalapril prazosin lysinopril minoxidil quinapril hydralazine cilazapril sodium nitroprusside nifedepine clonidine diltiazem methyldopa
  • Thrombolvtic urokinase streptokinase tissue plasminogen activator TAA
  • (l) R is selected from the group consisting of:
  • 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 monoalky
  • R 10 is lower alkyl, phenyl unsubstituted or substituted by lower alkyl, or -NHR ⁇
  • 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 substitute
  • R j is selected from the group consisting of: (a) hydrogen,
  • 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:
  • R 5 is selected from the group consisting of: (i) alkyl of from one to fifteen carbons, inclusive, 20 (ii)
  • R 5 is independently as defined above; (4) R ⁇ is independently selected from the group consist- ing of:
  • R 7 is independently selected from the group consisting of hydrogen, lower acyl, and lower alkyl
  • R 7 is independently as defined above and « is independently selected from the group consisting of hydrogen, lower alkyl, and benzyl,
  • 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.
  • Preferred compounds are as follows:

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte à un procédé de traitement de la resténose, l'athérosclérose ou l'hyperplasie néointime des muscles lisses vasculaires chez un patient en lui administrant des composés connus utiles comme inhibiteurs du sous-type de récepteur AT-2 de l'Angiotensine II.
PCT/US1993/000390 1992-02-14 1993-01-15 Procede de traitement de la proliferation de tissus anormaux par l'administration d'antagoniste de l'angiotensine ii Ceased WO1993015734A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP93903529A EP0625902A1 (fr) 1992-02-14 1993-01-15 Procede de traitement de la proliferation de tissus anormaux par l'administration d'antagoniste de l'angiotensine ii
JP5514070A JPH07503729A (ja) 1992-02-14 1993-01-15 アンギオテンシン２アンタゴニストの投与による異常な組織増殖の治療法

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US83744692A 1992-02-14 1992-02-14
US837,446 1992-02-14
US94259092A 1992-09-09 1992-09-09
US942,590 1992-09-09

Publications (1)

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WO1993015734A1 true WO1993015734A1 (fr) 1993-08-19

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PCT/US1993/000390 Ceased WO1993015734A1 (fr) 1992-02-14 1993-01-15 Procede de traitement de la proliferation de tissus anormaux par l'administration d'antagoniste de l'angiotensine ii

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EP (1) EP0625902A1 (fr)
JP (1) JPH07503729A (fr)
AU (1) AU3475693A (fr)
IL (1) IL104527A0 (fr)
WO (1) WO1993015734A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5663187A (en) * 1994-03-29 1997-09-02 Merck & Co., Inc. Treatment of atherosclerosis with angiotensin II receptor blocking imidazoles
EP0914828A3 (fr) * 1997-10-24 2000-03-01 National University Of Singapore Utilisation de des-aspartate-angiotensine I

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT2160190E (pt) * 2007-06-07 2016-01-27 Sigma Tau Ind Farmaceuti Derivados de 5beta, 14 beta-androstano úteis para o tratamento de doenças causadas por fibroses de órgão

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0245637A1 (fr) * 1986-04-01 1987-11-19 Warner-Lambert Company Dérivés de la 4,5,6,7-tétrahydro-1H-imidazo[4,5-c]pyridine et leurs analogues ayant une activité antihypertensive
EP0498361A2 (fr) * 1991-02-06 1992-08-12 Schering Corporation Association d'un antagoniste de l'angiotensine-II ou d'un inhibiteur de la rénine avec un inhibiteur de l'endopeptidase neutre

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0245637A1 (fr) * 1986-04-01 1987-11-19 Warner-Lambert Company Dérivés de la 4,5,6,7-tétrahydro-1H-imidazo[4,5-c]pyridine et leurs analogues ayant une activité antihypertensive
EP0498361A2 (fr) * 1991-02-06 1992-08-12 Schering Corporation Association d'un antagoniste de l'angiotensine-II ou d'un inhibiteur de la rénine avec un inhibiteur de l'endopeptidase neutre

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BIOMEDICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS vol. 179, no. 3, 1991, pages 1361 - 1367 M. VISWANATHAN ET AL. 'CHANGES IN EXPRESSION OF ANGIOTENSIN RECEPTOR SUBTYPES IN THE RAT AORTA DURING DEVELOPMENT' cited in the application *
HYPERTENSION vol. 20, no. 6, December 1992, pages 737 - 745 P. JANIAK ET AL. 'ROLE OF ANGIOTENSIN SUBTYPE 2 RECEPTOR IN NEOINTIMA FORMATION AFTER VASCULAR INJURY' *
JOURNAL OF MEDICINAL CHEMISTRY vol. 34, no. 11, 1991, pages 3248 - 3260 C.J. BLANKLEY ET AL. 'SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS OF A NOVEL SERIES OF NON-PEPTIDE ANGIOTENSIN II RECEPTOR BINDING INHIBITORS SPECIFIC FOR THE AT2 SUBTYPE' *
RECEPTOR vol. 1, no. 3, 1991, pages 133 - 140 A.T. CHIU ET AL. 'ANGIOTENSIN II-1 RECEPTORS MEDIATE BOTH VASOCONSTRICTOR AND HYPERTROPHIC RESPONSES IN RAT AORTIC SMOOTH MUSCLE CELLS' *
SUPPLEMENT TO HYPERTENSION vol. 18, no. 4, 1991, pages 1160 - 1164 W. OSTERRIEDER ET AL. 'ROLE OF ANGIOTENSIN II IN INJURY-INDUCED NEOINTIMA FORMATION IN RATS' *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5663187A (en) * 1994-03-29 1997-09-02 Merck & Co., Inc. Treatment of atherosclerosis with angiotensin II receptor blocking imidazoles
US5663186A (en) * 1994-03-29 1997-09-02 Merck & Co., Inc. Treatment of atherosclerosis with angiotensin II receptor blocking imidazoles
EP0914828A3 (fr) * 1997-10-24 2000-03-01 National University Of Singapore Utilisation de des-aspartate-angiotensine I
SG92610A1 (en) * 1997-10-24 2002-11-19 Univ Singapore The use of des-aspartate-angiotensin i as an agent for the treatment and prevention of neointima formation, restenosis, and arteriosclerosis

Also Published As

Publication number Publication date
AU3475693A (en) 1993-09-03
EP0625902A1 (fr) 1994-11-30
JPH07503729A (ja) 1995-04-20
IL104527A0 (en) 1993-05-13

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