WO1994007492A1 - Use of 4-hydrazono-1,4-dihydro-pyridine and/or 4-hydrazino-pyridine derivatives for treatment of hypertension and congestive heart failure - Google Patents

Use of 4-hydrazono-1,4-dihydro-pyridine and/or 4-hydrazino-pyridine derivatives for treatment of hypertension and congestive heart failure Download PDF

Info

Publication number
WO1994007492A1
WO1994007492A1 PCT/US1993/008156 US9308156W WO9407492A1 WO 1994007492 A1 WO1994007492 A1 WO 1994007492A1 US 9308156 W US9308156 W US 9308156W WO 9407492 A1 WO9407492 A1 WO 9407492A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
hydrazino
sulfonyl
acid
biphenyl
Prior art date
Application number
PCT/US1993/008156
Other languages
French (fr)
Inventor
Paul Kosta Tomich
Michael John Bohanon
Michael S. Lajiness
Yoshiji Fujita
Kazuo Tsuzuki
Original Assignee
The Upjohn Company
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 The Upjohn Company filed Critical The Upjohn Company
Priority to AU50968/93A priority Critical patent/AU5096893A/en
Publication of WO1994007492A1 publication Critical patent/WO1994007492A1/en

Links

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

Definitions

  • the present invention provides a new use of known compounds. More particularly, the present invention provides for the use of 4-hydrazono-l,4-dihydro-pyridine and 4-hydrazino- pyridine derivatives for the treatment of hypertension and congestive heart failure.
  • Angiotensin II the primary biologically active octapeptide of the renin-angiotensin- aldosterone (RAA) system, elicits a variety physiological effects, including arteriolar vasoconstriction, aldosterone biosynthesis and secretion, catecholamine release, stimulation of drinking behavior, glycogenolysis and alteration of renal function through activation of the appropriate receptor in the vasculature, adrenal cortex, adrenal medulla, brain, liver and kidney, respectively (A. T. Chiu et al., Biochem. Biophys. Res. Commun., 165, 196, 1989).
  • ACE angiotensin converting enzyme
  • the ACE inhibitors exhibit a non-specific contribution to the hydrolysis of the other substrates outside the RAA system, such as bradykinin, enkephalins, substance P, etc. Possibly due to the bradykinin potentiation, such adverse reaction as dry cough was associated with ACE inhibitors.
  • ACE renin
  • angiotensin II antagonists are considered to be the most promising approach to intervening in the RAA system.
  • the putative peptidic angiotensin II antagonist Saralasin has been available for over 30 years. However, its therapeutic use has been severely limited by its partial agonistic action, short plasma half-life and lack of oral activity.
  • the head part imidazole ring of DuP 753 was found to be replaceable by benzimidazole (EP-392,317, EP-399,732, EP-400,835) or imidazopyridine ring (EP-399,731, EP-400,974, EP- 415,866). Recently, pyridine or quinoline derivatives were also discovered by ICI (D-8731; EP- 412,848, EP-456,442, WO-91/7404, EP-453,210) and by Meiji Seika (WO-91/19697).
  • the present invention provides certain 4-hydrazono-l,4-dihydro-pyridine derivatives, previously known as dyes and contract control agents, which possess angiotensin II antagonistic activity and are thus useful to treat hypertension.
  • the present invention provides a method for treating or preventing diseases caused by the improper functioning of the renin-angiotensin-aldosterone system comprising the systemic administration of an amount effective to inhibit the angiotensin II receptor of a compound of the formula [I] or [II], or a pharmacologically acceptable salt or ester thereof:
  • the formed ester there are methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, t-butoxycarbonyl, 2- hydroxyethoxycarbonyl or 3-hydroxypropoxycarbonyl, in case R , R , R , R 5 , R 6 has carboxylic acid substituent.
  • R , R , R , R 5 , R 6 has carboxylic acid substituent.
  • acetoxy, n-propionyl, butyryl, valeryl or hexanoyl in case substituent is a hydroxyl group.
  • aryl include phenyl, biphenyl, and substituted derivatives thereof.
  • the 4-hydrazono-l,4-dihydro-pyridine/4-hydrazino-pyridine derivatives of the present invention can form a pharmacologically acceptable alkali metal salt as a part of R 1 , R 2 , R , R- and R 6 when substituted by -SO3H, -C0 2 H or tetrazole.
  • salts as a part of amine moiety within the 4-hydrazono-l,4-dihydro-pyridine/4-hydrazino-pyridine structures, there are hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, acetate, propionate, lactate, maleate, succinate, tartrate and the like.
  • the compounds of the present invention are useful whenever it is medically necessary or desirable to inhibit the renin-angiotensin-aldosterone system.
  • the angiotensin II receptor antagonist compounds of the present invention are thus administered to humans to treat or prevent a variety of cardiovascular disorders related to the improper functioning of the renin- angiotensin-aldosterone system including hypertension, congestive heart failure, renal failure, glaucoma, or hyperuricemia. Such conditions are readily apparent to an ordinarily skilled physician. Treatment or prevention of hypertension or congestive heart failure are the preferred cause of using these compounds.
  • treat is meant the partial or total alleviation of the symptoms of the disease manifested in the patient.
  • prevent is meant the partial or total avoidance of the symptoms of the disease in a patient who is otherwise believed by the physician to be susceptible to such disease or conditioa
  • the 4-Hydrazono-l,4-dihydro-pyridine and/or 4-hydrazino-pyridine derivatives or pharmacologically acceptable esters or salts thereof are administered orally, parenterally by insufflation, rectally, locally.
  • Parenteral administration includes subcutaneous, intravenous, intramuscular, intranasal administration or injection.
  • Dose to be administered an adult is in a range of 1 to 500 mg/day. The exact dose can be selected from the above range, taking into account the age of patient, weight, condition to be treated and route of administration into consideration.
  • the frequency of administration is usually one to four times a day.
  • the 4-hydrazono-l,4-dihydro-pyridine/4-hydrazino-pyridine derivatives or pharmacologically acceptable ester or salts thereof can be formulated, by a conventional method, into a dosage unit forms such as tablets, capsules, pills, powder, granules, powder packet, cachets, sterile parenteral solution or suspensions, eyedrops, solutions or suspensions, elixirs, suppositories, aerosols and emulsions which contains them in a predetermined amount.
  • solid or fluid unit dosage form can be prepared.
  • the active compound is mixed with an excipient or a carrier such as magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulphate, starch, lactose, acacia, ethyl cellulose and the like.
  • a capsule agent is prepared by mixing the compound of the present invention with an inert pharmaceutical excipient, filling the mixture into a hard gelatin capsule having suitable size.
  • a soft gelatin capsule is prepared by machine capsulation of slurry composed of the compound, suitable vegetable oil, light petrolatum or other inert oil.
  • the compound of the present invention is dissolved in an aqueous vehicle together with sugar, aromatic flavor and preservative to obtain a syrup.
  • Elixirs are prepared using an alcoholic vehicle such as ethanol, a sweetener such as sugar and saccharin as well as a flavor.
  • Suspensions are prepared using a suspending agent such as acacia, tragacanth or methyl cellulose and an aqueous vehicle.
  • a fluid unit dosage form is prepared using the compound of the present invention and a sterile vehicle.
  • a vehicle such as water, Ringer's solution, isotonic sodium chloride solution and the concentration to be used
  • the compoimd is suspended or dissolved in the vehicle.
  • the compoimd is dissolved in water for injection, and this is sterile filtered, filled into a vial for an ampoule, and sealed.
  • an adjuvant such as local anesthetic, preservative and buffer is dissolved in vehicle.
  • a lyophilized powder having good shelf stability can be prepared. In the case of this formulation, the powder is reconstituted upon use.
  • Parenteral suspensions can be similarly prepared using the compound of the present invention.
  • the compound of the present invention can be sterilized by exposure to ethylene oxide before suspended in a sterile vehicle.
  • a surfactant or a wetting agent is added to facilitate dispersion of the compound.
  • the compound of the present invention can be formulated into a local dosage form in combination with a suitable carrier for local administration.
  • a suitable carrier for local administration.
  • a carrier to be used are cream, ointment, lotion, paste, jelly, spray, aerosol and the like.
  • suppositories can be prepared.
  • a base are cacao butter, polyethylene glycol, polyethylene sorbitan monostearate and the like.
  • 4-Hydrazono-l,4-dihydro-pyridine/4-hydrazino-pyridine derivatives represented by the general formula [I] are well known, readily available compounds and can be purchased from standard chemical manufacturers such as Eastman Kodak, and/or can be prepared by known means, see, e.g., U.S. Patents 4,152,152 and 3,622,327 and EPA 247845. They can be prepared, for example, according to the following scheme. (See Chart A).
  • General formula [I] can be prepared according to the procedures reported by H. Vorbriiggen, Synthesis 301 (1973) by reacting the appropriate 4-pyridones (1) or 4- hydroxypyridines (3) with optionally substituted hydrazines.
  • the compounds [I] can be obtained by alkylation, acylation or sulfonylation of the corresponding hydrazones (2) or hydrazines which are formed from the reaction of (1) or (3) with hydrazine.
  • 4-Hydroxypyridines can be converted to 4-halogeno-pyridines by reacting with phosphorus tri-or penta-halides, phosphoryl chloride or thionylchloride [K. Heyns and G. Vogelsang, Chem. Ber. 87:13 (1954)] which can be subsequently converted to the claimed compounds, according to the procedures reported by D. S. Tarbell, et al., J. Am. Chem. Soc. 70:1381 (1948).
  • 4-Aminoquinoline derivatives are prepared from the corresponding 4-quinolone through chlorination by phosphorus oxychloride followed by animation with ammonia in thermal conditions.
  • 4-Hydrazono-l,4-dihydro-pyridine and/or 4-hydrazino-pyridine derivatives were also easily prepared by similar reactions.
  • Rat liver homogenates are prepared as follows: Adult rats (10-25) are decapitated and the livers excised free of connective tissue. They are held in a container of cold 0.05 M TRIS buffer (pH8.). Four to six livers are placed in a waring blender, covered with fresh cold Tris buffer, and homogenized. This material is then further homogenized with the glass homogenizer and filtered through a four layer thickness of gauze into 250 mL centrifuge bottles on ice. This procedure is repeated until four bottles have been filled. The material is centrifuged in a swinging bucket rotor for 30 min at 1500 g(max), 4°C.
  • the material that has floated to the surface is collected using a spatula and resuspended in about 8 mL of TRIS buffer. This material is then placed in a 50 mL syringe, passed through a 20G needle and pipetted in 0.1, 0.5, and 1.0 aliquots into eppendorf tubes. The protein concentration is also ascertained. These tubes are frozen in dry ice-acetone and stored at -80 C.
  • 25uL of the 0.05 M TRIS buffer is added to the wells in the counter designated for Total Binding (TB).
  • 25 ⁇ L of 10 ⁇ M ang II are added to the control wells designated for Non- Specific Binding (NSB) usually and 25 ⁇ L of the 5 nM angll is added to wells as experimental controls.
  • the rat liver homogenate is removed from the -80°C freezer and thaw on ice.
  • the homogenate is diluted with angll assay buffer to a protein concentration of ca. 0.1 mg/mL.
  • 100 ⁇ L of this diluted receptor source is added to all wells containing 25 ⁇ L of dispensed samples to test. (After addition of ligand, the protein concentration is about 45 ng/mL). 11 mL of diluted receptor is prepared per assay plate.
  • Radioligand is prepared using - I-angII (50 ⁇ C j /mL; 2,000 mC j ⁇ mmole) and unlabeled 100 nM angll.
  • Per assay plate 172 ⁇ L of the first and 26 ⁇ L of the second are diluted with 12.8 mL of angll assay buffer. 125 ⁇ L of this material is added per well in the assay plate. (This will give an angll concentration inithe assay of ca. 0.25 nM, lower than the Kd for this compound, but sufficient to provide a good indication of antagonism.)
  • the total added cpm generally runs around 100,000 to 130,000.
  • the sequence of addition for the materials is sample to be tested, rat liver homogenate and finally the ligand. By adding in this sequence, sufficient initial mixing occurs that stirring or shaking is not necessary.
  • the plates are then incubated for 2 hours at 37° C in a humidified incubator. After this time, samples are collected on Printed Filter Mat B using the Skatron MicroCell Harvester. Care should be taken that the filter mats and assay plates are oriented correctly.
  • the filter mats are dried at room temperature in a circulated air drying oven. The mats are bagged, the long side sealed, and one end cut. To this cut end one adds ca. 20 mL of scintillation fluid.
  • a rectangular strip-like sample of thoracic aorta isolated from an anesthetized rabbit was prepared, and this was suspended at 2.0 gr of loaded tension in Magnus tube filled with Krebs- Henseleitoid nutrition solution which was well aerated with 95% 0 2 - 5% C0 2 , and the constriction tension was measured using an isometric transducer. After the tension of the sample at rest became stable, accumulative administration of Ang II was carried out to obtain a concentration-action curve. Thereafter, the sample was washed with the same nutrition solution, and then 10 "5 - 10 "6 M test compound was treated for 20 min. to obtain again a concentration- action curve of Ang II.
  • compounds of the present invention showed Ang II antagonistic activity. All of the compounds 1-36 listed herein showed activity in one or both of these tests. For example, the compound No. 23 and 27 showed 90 and 82% inhibition in Test 1, respectively. And the compounds No. 23 and 27 showed pA 2 value of 5.51 and 5.32 in test 2, respectively.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides the use of certain known 4-hydrazono-1,4-dihydro-pyridine and 4-hydrazino pyridine compounds for the treatment of hypertension and congestive heart failure.

Description

USE OF 4-HYDRAZONO-l,4-DIHYDRO-PYRIDINE AND/OR 4-HYDRAZINO-PYRIDINE DERIVATIVES FOR TREATMENT OF HYPERTENSION AND CONGESTIVE HEART FAILURE BACKGROUND OF THE INVENTION The present invention provides a new use of known compounds. More particularly, the present invention provides for the use of 4-hydrazono-l,4-dihydro-pyridine and 4-hydrazino- pyridine derivatives for the treatment of hypertension and congestive heart failure.
Angiotensin II, the primary biologically active octapeptide of the renin-angiotensin- aldosterone (RAA) system, elicits a variety physiological effects, including arteriolar vasoconstriction, aldosterone biosynthesis and secretion, catecholamine release, stimulation of drinking behavior, glycogenolysis and alteration of renal function through activation of the appropriate receptor in the vasculature, adrenal cortex, adrenal medulla, brain, liver and kidney, respectively (A. T. Chiu et al., Biochem. Biophys. Res. Commun., 165, 196, 1989). During the past decade, a breakthrough in hypertension treatment has been achieved by the discovery of the angiotensin converting enzyme (ACE) inhibitors, such as captopril or enalapril, or the renin inhibitors.
Although understanding of the causal role of the RAA system in the mosaic of essential hypertension is still incomplete, the RAA system, which is a closed-loop, negative-feedback system reacting to a reduction in renal per usion or excessive loss of sodium, seems to be critically involved in the development and maintenance of hypertension as well as in congestive heart failure. The evidence supporting this involvement of RAA system in essential hypertension has been collected through therapeutic research using the ACE inhibitors (Tips, July 1989, Vol. 10, p. 273).
However, the ACE inhibitors exhibit a non-specific contribution to the hydrolysis of the other substrates outside the RAA system, such as bradykinin, enkephalins, substance P, etc. Possibly due to the bradykinin potentiation, such adverse reaction as dry cough was associated with ACE inhibitors. Not only ACE but also renin was shown to have other substrates outside the RAA system. In this context, angiotensin II antagonists are considered to be the most promising approach to intervening in the RAA system. The putative peptidic angiotensin II antagonist Saralasin has been available for over 30 years. However, its therapeutic use has been severely limited by its partial agonistic action, short plasma half-life and lack of oral activity. Since the discovery of a "non-peptide" angiotensin II antagonist by Takeda (Japan Kokai Patent 1797-148,788, 1981-71,073 1982- 98,270, 1983-157,768), extensive efforts have been made to modify or optimize this prototype lead, especially by DuPont. As a result of such efforts, orally active, competitive angiotensin II antagonist DuP 753 was discovered. The structure of this compound is set forth below.
Figure imgf000004_0001
The head part imidazole ring of DuP 753 was found to be replaceable by benzimidazole (EP-392,317, EP-399,732, EP-400,835) or imidazopyridine ring (EP-399,731, EP-400,974, EP- 415,866). Recently, pyridine or quinoline derivatives were also discovered by ICI (D-8731; EP- 412,848, EP-456,442, WO-91/7404, EP-453,210) and by Meiji Seika (WO-91/19697).
Figure imgf000004_0002
Surprisingly, the present invention provides certain 4-hydrazono-l,4-dihydro-pyridine derivatives, previously known as dyes and contract control agents, which possess angiotensin II antagonistic activity and are thus useful to treat hypertension.
INFORMATION DISCLOSURE 4-Hydrazono-l,4-dihydro-pyridines are well known as dyes and contrast control agents
(see, e.g., U.S. Patents 4,152,152 and 3,622,327 and EPA 247845). These compounds have not been reported as useful for the treatment of hypertension or congestive heart failure.
SUMMARY OF THE INVENTION The present invention provides a method for treating or preventing diseases caused by the improper functioning of the renin-angiotensin-aldosterone system comprising the systemic administration of an amount effective to inhibit the angiotensin II receptor of a compound of the formula [I] or [II], or a pharmacologically acceptable salt or ester thereof:
Figure imgf000004_0003
wherein each occurrence of R , R , R and R is the same or different and is
(a) hydrogen,
(b) -Cjo alkyl, (c) C2-C2o alkenyl,
(d) -(CH2)n-OR7,
(e) -(CH2)n-CONR7R8,
(f) aryl, or (g) arylalkyl, or wherein
(h) R1 and R , or R4 and R taken together form a five or six-membered aromatic or non-aromatic ring having 0 to 2 ring members selected from sulfur or nitrogen, said ring optionally substituted by
Figure imgf000005_0001
(x) -(CH2)n-NR7R8, (xi) S03R7, or (xii) S02NR7R8; wherein each occurrence of R and R is the same or different and is
(a) hydrogen,
(b) CrC8 alkyl,
(c) C2-C8 alkenyl, (d) aryl, or
(e) arylalkyl, or
(f) wherein R 7 and R 8 taken together form a five or six-membered ring; wherein RJ is
(a) hydrogen, (b) CrC20 alkyl,
(c) -(CH2)n+1-C02R7,
(d) -(CH2)n+1-CONR7R8,
(e) aryl, or
(f) arylalkyl; wherein R6is
(a) CrC20 alkyl, (b) aryl, or
(c) biphenyl, or
(d) arylalkyl; wherein X is (a) a bond,
(b) CH2-,
(c) -CO-
(d) -S02- or,
(e) -SO-; wherein n is an integer from 0 to 3. Preferred compounds include:
1) 4-[(2-Ethyl-l-methyl-4(lH)-quinolinylidene)hydrazino]benzoic acid
2) 4'-[(2-Ethyl-l-methyl-4(lH)-quinolinylidene)hydrazino]-[l,l '-biphenyl]-2-carboxylic acid
3) 4'-[[(l-Methyl-2-propyl-4(lH)-quinolinylidene)hydrazino]methyl]-[l,r-biphenyl]-2- carboxylic acid
4) 4-[[(2-Butyl- l-methyl-4(lH)-quinolinylidene)hydrazino]sulfonyl]benzoic acid
5) 4'- [[(2-Ethyl- 1 -methyl-4( lH)-quinolinylidene)hydrazino]sulfonyl]-[ 1 , 1 '-biphenyl]-2- carboxylic acid
6) Benzen-l,4-dicarboxylic acid, 4-(l-methyl-2-propyl-4(lH)-quinolinylidene)hydrazide 7) [l,r-Biphenyl]-2,4'-dicarboxylic acid, 4'-[l,2-dimethyl-4(lH)-quinolinylidene)hydrazide
8) 2-Ethyl-l-methyl-4(lH)-quinolinone, t2'-(lH-tetrazol-5-yl)[l,r-biphenyl]-4-yl]hydrazone
9) l-Methyl-2-propyl-4(lH)-quinolinone, [[2'-(lH-tetrazol-5-yl)[l,l '-biphenyl]-4- yl]methyl]hydrazone
10) 2-Ethyl-l-methyl-4(lH)-quinolinone, [[2'-(lH-tetrazol-5-yl)[l,l '-biphenyI]-4- yl]sulfonyl]hydrazide
11) 4-[ 1 ,2,6-Trimethyl-4-(lH)-pyridinylidene)hydrazino]benzoic acid
12) 4-[ l-Benzyl-2,6-dimethyl-4(lH)-pyridinylidene)hydrazino]benzoic acid
13) 4-[(2,6-Dimethyl-l-phenyl-4(lH)-pyridinylidene)hydrazino]benzoic acid
14) 3-[[(l,2,6-Trimethyl-4(lH)-pyridinylidene)hydrazino]sulfonyl]benzoic acid 15) 4'-[[(l,2,6-Trimethyl-4(lH)-pyridinylidene)hydrazino]sulfonyl]-[l,l '-biphenyl] -2- carboxylic acid
16) 4'-[[(l-Benzyl-2,6-dimethyl-4(lH)-pyridinylidene)hydrazino]sulfonyl]-[l,l'biphenyl]-2- carboxylic acid
17) 4-f[(4-Carboxyphenyl)sulfonyl]hydrazono]-l,4-dihydro-l,2,6-trimethyl-pyridine-3- carboxylic acid
18) 4-[[(4-Carboxyphenyl)sulfonyl]hydrazono]-l,4-dihydro-l,2,6-trimethyl-3-pyridineacetic acid
19) [ 1,1 '-Biphenyl]-2,4'-dicarboxylic acid, 4'-(2,6-diethyl-l-methyI-4(lH)- pyridinylidene)hydrazide
20) 4'-[[(2,6-diethyl-l-methyl-4(lH)-pyridinylidene)hydrazino]methyl-[l,l'-biphenyl]-2- carboxylic acid
21) l,2,6-Trimethyl-4(lH)-pyridone, [[2'-(lH-tetrazol-5-yl)[l,l '-biphenyl]-4- yl]sulfonyl]hydrazide
22) 2,6-Diethyl-l-methyl-4(lH)-pyridone, [[2'-(lH-tetrazol-5-yl)[l,l '-biphenyl]-4- yl]methyl]hydrazide 23) 4-(hexadecyloxy)-3-[[[2-(4-methoxy-m-tolyl)-l-methyl-6-sulfo-4(lH)- quinolylidene]hydra-zino]sulfonyl]-benzoic acid
24) 3-[[[2-(4-ethoxy-3-methoxyphenyl)-l-methyl-6-sulfo-4(lH)-quinolinylidene]hydrazino]- sulfonyl]-4-(hexadecyloxy)-benzoic acid
25) 1 ,4-dihydro- 1 -methyl-4-oxo-2-[p-(p-tolyloxy)phenyl]-6-quinolinesulfonic acid, (hexadecylsulfonyl)hydrazone
26) 3-[[[2-(p-carboxyphenyl)-l-methyl-6-sulfo-4(lH)-quinolylidene]hydrazino]sulfonyl]-4- (hexadecyloxy)-benzoic acid
27) 4-(hexadecyloxy)-3-[[[l-methyl-2-[p-(phenylsulfonyl)phenyl]-6-sulfo-4(lH)- quinolinylidene]-hydrazino]sulfonyl]-benzoic acid 28) 4-(hexadecyloxy)-3-[[(l-methyl-2-phenyl-6-sulfo-4(lH)- quinolylidene)hydrazino]sulfonyI]-benzoic acid
29) 4-(hexadecyloxy)-3-[[(l-methyl-6-sulfo-2-m-tolyl-4(lH)- quinolylidene)hydrazineo]sulfonyl]-benzoic acid
30) l,4-dihydro-l-methyl-4-oxo-2-phenyl-6-quinolinesulfonic acid, [[m- (hexadecylmethylsulfamoyl)phenyl]sulfonyl]-hydrazone
31) [p-[[[2-[p-(hexadecyloxy)phenyl]-l-methyl-6-sulfo-4(lH)- quinolinylidene]hydrazino]sulfonyl]phenoxy]-acetic acid
32) [6-acetamido-l-methyl-2-(p-sulfophenyl)-4(lH)-quinolyidene]hydrazide hexadecanesulfonic acid, sodium salt 33) 2-(3,4-dimethoxyphenyl)-l,4-dihydro-l-methyl-4-oxo-6-quinolinesulfonic acid, (hexadecylsulfonyl)hydrazone
34) 5-[[[2-[p-(hexadecyloxy)phenyI]-l-meftyl-6-sulfo-4(lH)- quinolylidene]hydrazino]sulfonyl] -salicylic acid
35) 4-[(hexadecylsulfonyl)-hydrazono]- l-methyl-2-phenyl-5-quinolinesulfonic acid 36) 2-(2-fluorophenyl)-4-[(hexadecylsulfonyl)hydrazono]-l ,4-dihydro- l-methyl-6- quinolinesulfonic acid The 4-hydrazono-l,4-dihydro-pyridine/4-hydrazino-pyridine derivatives of the present invention can form a pharmacologically acceptable ester at a part of R1, R2, R4, R5 and R6 in the general formula [I]. As examples of the formed ester, there are methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, t-butoxycarbonyl, 2- hydroxyethoxycarbonyl or 3-hydroxypropoxycarbonyl, in case R , R , R , R5, R6 has carboxylic acid substituent. There are acetoxy, n-propionyl, butyryl, valeryl or hexanoyl, in case substituent is a hydroxyl group. Examples of aryl include phenyl, biphenyl, and substituted derivatives thereof.
Further, the 4-hydrazono-l,4-dihydro-pyridine/4-hydrazino-pyridine derivatives of the present invention can form a pharmacologically acceptable alkali metal salt as a part of R1, R2, R , R- and R6 when substituted by -SO3H, -C02H or tetrazole. As examples of salts as a part of amine moiety within the 4-hydrazono-l,4-dihydro-pyridine/4-hydrazino-pyridine structures, there are hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, acetate, propionate, lactate, maleate, succinate, tartrate and the like. The compounds of the present invention are useful whenever it is medically necessary or desirable to inhibit the renin-angiotensin-aldosterone system. The angiotensin II receptor antagonist compounds of the present invention are thus administered to humans to treat or prevent a variety of cardiovascular disorders related to the improper functioning of the renin- angiotensin-aldosterone system including hypertension, congestive heart failure, renal failure, glaucoma, or hyperuricemia. Such conditions are readily apparent to an ordinarily skilled physician. Treatment or prevention of hypertension or congestive heart failure are the preferred cause of using these compounds.
By "treat" is meant the partial or total alleviation of the symptoms of the disease manifested in the patient. By "prevent" is meant the partial or total avoidance of the symptoms of the disease in a patient who is otherwise believed by the physician to be susceptible to such disease or conditioa
The 4-Hydrazono-l,4-dihydro-pyridine and/or 4-hydrazino-pyridine derivatives or pharmacologically acceptable esters or salts thereof are administered orally, parenterally by insufflation, rectally, locally. Parenteral administration includes subcutaneous, intravenous, intramuscular, intranasal administration or injection. Dose to be administered an adult is in a range of 1 to 500 mg/day. The exact dose can be selected from the above range, taking into account the age of patient, weight, condition to be treated and route of administration into consideration. The frequency of administration is usually one to four times a day.
The 4-hydrazono-l,4-dihydro-pyridine/4-hydrazino-pyridine derivatives or pharmacologically acceptable ester or salts thereof can be formulated, by a conventional method, into a dosage unit forms such as tablets, capsules, pills, powder, granules, powder packet, cachets, sterile parenteral solution or suspensions, eyedrops, solutions or suspensions, elixirs, suppositories, aerosols and emulsions which contains them in a predetermined amount.
For oral administration, solid or fluid unit dosage form can be prepared. For preparing solid composition, the active compound is mixed with an excipient or a carrier such as magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulphate, starch, lactose, acacia, ethyl cellulose and the like. A capsule agent is prepared by mixing the compound of the present invention with an inert pharmaceutical excipient, filling the mixture into a hard gelatin capsule having suitable size. A soft gelatin capsule is prepared by machine capsulation of slurry composed of the compound, suitable vegetable oil, light petrolatum or other inert oil.
For preparing a fluid composition, the compound of the present invention is dissolved in an aqueous vehicle together with sugar, aromatic flavor and preservative to obtain a syrup. Elixirs are prepared using an alcoholic vehicle such as ethanol, a sweetener such as sugar and saccharin as well as a flavor. Suspensions are prepared using a suspending agent such as acacia, tragacanth or methyl cellulose and an aqueous vehicle.
For parenteral administration, a fluid unit dosage form is prepared using the compound of the present invention and a sterile vehicle. Depending upon a vehicle such as water, Ringer's solution, isotonic sodium chloride solution and the concentration to be used, the compoimd is suspended or dissolved in the vehicle. For preparing solutions, the compoimd is dissolved in water for injection, and this is sterile filtered, filled into a vial for an ampoule, and sealed. Advantageously, an adjuvant such as local anesthetic, preservative and buffer is dissolved in vehicle. Alternatively, a lyophilized powder having good shelf stability can be prepared. In the case of this formulation, the powder is reconstituted upon use. Parenteral suspensions can be similarly prepared using the compound of the present invention. In the case of this formulation, the compound of the present invention can be sterilized by exposure to ethylene oxide before suspended in a sterile vehicle. Advantageously, a surfactant or a wetting agent is added to facilitate dispersion of the compound.
Alternatively, the compound of the present invention can be formulated into a local dosage form in combination with a suitable carrier for local administration. Examples of a carrier to be used are cream, ointment, lotion, paste, jelly, spray, aerosol and the like.
Further, when other form cannot be administered, suppositories can be prepared. Examples of a base are cacao butter, polyethylene glycol, polyethylene sorbitan monostearate and the like.
4-Hydrazono-l,4-dihydro-pyridine/4-hydrazino-pyridine derivatives represented by the general formula [I] are well known, readily available compounds and can be purchased from standard chemical manufacturers such as Eastman Kodak, and/or can be prepared by known means, see, e.g., U.S. Patents 4,152,152 and 3,622,327 and EPA 247845. They can be prepared, for example, according to the following scheme. (See Chart A).
General formula [I] can be prepared according to the procedures reported by H. Vorbriiggen, Synthesis 301 (1973) by reacting the appropriate 4-pyridones (1) or 4- hydroxypyridines (3) with optionally substituted hydrazines. Alternatively, as stepwise methods, the compounds [I] can be obtained by alkylation, acylation or sulfonylation of the corresponding hydrazones (2) or hydrazines which are formed from the reaction of (1) or (3) with hydrazine.
4-Hydroxypyridines can be converted to 4-halogeno-pyridines by reacting with phosphorus tri-or penta-halides, phosphoryl chloride or thionylchloride [K. Heyns and G. Vogelsang, Chem. Ber. 87:13 (1954)] which can be subsequently converted to the claimed compounds, according to the procedures reported by D. S. Tarbell, et al., J. Am. Chem. Soc. 70:1381 (1948).
4-Aminoquinoline derivatives are prepared from the corresponding 4-quinolone through chlorination by phosphorus oxychloride followed by animation with ammonia in thermal conditions. 4-Hydrazono-l,4-dihydro-pyridine and/or 4-hydrazino-pyridine derivatives were also easily prepared by similar reactions.
DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples further illustrate the present invention in detail but are not to be construed to limit the scope thereof. The Pharmacological evaluation of the compounds of the present invention is described hereinafter.
TEST 1 In vitro Ang II receptor binding assay
Rat liver homogenates are prepared as follows: Adult rats (10-25) are decapitated and the livers excised free of connective tissue. They are held in a container of cold 0.05 M TRIS buffer (pH8.). Four to six livers are placed in a waring blender, covered with fresh cold Tris buffer, and homogenized. This material is then further homogenized with the glass homogenizer and filtered through a four layer thickness of gauze into 250 mL centrifuge bottles on ice. This procedure is repeated until four bottles have been filled. The material is centrifuged in a swinging bucket rotor for 30 min at 1500 g(max), 4°C. The supernatant is carefully decanted and the pellet is resuspended in 0.05M TRIS (pH8.0) and resuspended with the glass homogenizer to reduce large clumps. Sucrose solution (69-70%) is added to the liver homogenate until the final concentration is ca. 44% (w/w). This solution is dispensed into Beckman ultracentrifuge tubes, about 28-30 mL per tube. These solutions are carefully overlayed with 10 mL of a 42.3% sucrose solution (w/w). This material is centrifuged for 120 min at 25,000 rpm in an SW28 rotor. The material that has floated to the surface is collected using a spatula and resuspended in about 8 mL of TRIS buffer. This material is then placed in a 50 mL syringe, passed through a 20G needle and pipetted in 0.1, 0.5, and 1.0 aliquots into eppendorf tubes. The protein concentration is also ascertained. These tubes are frozen in dry ice-acetone and stored at -80 C.
25uL of the 0.05 M TRIS buffer is added to the wells in the counter designated for Total Binding (TB). 25 μL of 10 μM ang II are added to the control wells designated for Non- Specific Binding (NSB) usually and 25 μL of the 5 nM angll is added to wells as experimental controls. The rat liver homogenate is removed from the -80°C freezer and thaw on ice. The homogenate is diluted with angll assay buffer to a protein concentration of ca. 0.1 mg/mL. 100 μL of this diluted receptor source is added to all wells containing 25 μL of dispensed samples to test. (After addition of ligand, the protein concentration is about 45 ng/mL). 11 mL of diluted receptor is prepared per assay plate.
I OC
Radioligand is prepared using - I-angII (50 μCj/mL; 2,000 mCj\mmole) and unlabeled 100 nM angll. Per assay plate, 172 μL of the first and 26 μL of the second are diluted with 12.8 mL of angll assay buffer. 125 μL of this material is added per well in the assay plate. (This will give an angll concentration inithe assay of ca. 0.25 nM, lower than the Kd for this compound, but sufficient to provide a good indication of antagonism.) The total added cpm generally runs around 100,000 to 130,000.
The sequence of addition for the materials is sample to be tested, rat liver homogenate and finally the ligand. By adding in this sequence, sufficient initial mixing occurs that stirring or shaking is not necessary. The plates are then incubated for 2 hours at 37° C in a humidified incubator. After this time, samples are collected on Printed Filter Mat B using the Skatron MicroCell Harvester. Care should be taken that the filter mats and assay plates are oriented correctly. The filter mats are dried at room temperature in a circulated air drying oven. The mats are bagged, the long side sealed, and one end cut. To this cut end one adds ca. 20 mL of scintillation fluid. Scintillant is distributed over the entire filter using a roller, the end resealed and placed into holders for counting on the LKB Beta-Plate using program 7. Again, care should be taken as to the correct orientation of the filter mat. The data are captured both on a 3.5" floppy disc and on paper. TEST 2 In vitro antagonism to Ang π constriction in an isolated rabbit thoracic aorta.
A rectangular strip-like sample of thoracic aorta isolated from an anesthetized rabbit was prepared, and this was suspended at 2.0 gr of loaded tension in Magnus tube filled with Krebs- Henseleitoid nutrition solution which was well aerated with 95% 02 - 5% C02, and the constriction tension was measured using an isometric transducer. After the tension of the sample at rest became stable, accumulative administration of Ang II was carried out to obtain a concentration-action curve. Thereafter, the sample was washed with the same nutrition solution, and then 10"5 - 10"6 M test compound was treated for 20 min. to obtain again a concentration- action curve of Ang II. The results were obtained as follows: generated maximum tension at the first accumulative administration of Ang II was regarded as 100%, and the 50% effective concentration (ED5Q) was obtained in the presence or absence of the test compound, and pA2 value was calculated according to the following equations:
PA2=-logKB KB=C/{(A'/A)-1 } C: concentration of the test compound (M)
A': ED50 in the presence of test compound (M)
A: Ed50 in the absence of the test compound (M)
In above tests, compounds of the present invention showed Ang II antagonistic activity. All of the compounds 1-36 listed herein showed activity in one or both of these tests. For example, the compound No. 23 and 27 showed 90 and 82% inhibition in Test 1, respectively. And the compounds No. 23 and 27 showed pA2 value of 5.51 and 5.32 in test 2, respectively.
CHART A
Figure imgf000013_0001
Figure imgf000013_0003
Figure imgf000013_0002
Figure imgf000013_0004

Claims

1. Use of a 4-hydrazono-l,4-dihydro-pyridine and/or 4-hydrazino-pyridine derivative of the formula [I] or [II]
Figure imgf000014_0001
or a pharmacologically acceptable salt of ester thereof, wherein each occurrence of R , R , R and R is the same or different and is
(a) hydrogen,
(b) CJ-CJO alkyl, (c) C2-C20 alkenyl,
(d) -(CH2)n-OR7,
(e) -(CH2)n-CONR7R8,
(f) aryl, or
(g) arylalkyl, or wherein (h) R and R , or R and R taken together form a five or six-membered aromatic or non-aromatic ring having 0 to 2 ring members selected from sulfur or nitrogen, said ring optionally substituted by
Figure imgf000014_0002
(xii) S02NR7R8; wherein each occurrence of R and R8 is the same or different and is (a) hydrogen, (b) CrC8 alkyl,
(c) C2-C8 alkenyl,
(d) aryl, or
(e) arylalkyl, or (f) wherein R 7' and R 8° taken together form a five or six-membered ring; wherein RJ is
(a) hydrogen,
(b) CrC20 alkyl,
(c) -(CH2)n+1-C02R7, (d) -(CH2)n+1-CONR7R8,
(e) aryl, or
(f) arylalkyl; wherein R is
(a) CrC20 alkyl, (b) aryl, or
(c) biphenyl, or
(d) arylalkyl; wherein X is
(a) a bond, (b) CH2-,
(c) -CO-
(d) -S02- or,
(e) -SO-; wherein n is an integer from 0 to 3 to prepare a medicament to treat or prevent diseases caused by the improper functioning of the renin-angiotensin-aldosterone system.
2. A use of claim 1, wherein the disease is hypertension.
3. A use of claim 1, wherein the disease is congestive heart failure.
4. A use of claim 1, wherein the compound is selected from the group consisting of:
1) 4-[(2-Ethyl-l-methyl-4(lH)-quinolinylidene)hydrazino]benzoic acid
2) 4'-[(2-Ethyl-l-methyl-4(lH)-quinolinylidene)hydrazino]-[l,l'-biphenyl]-2- carboxylic acid 3) 4'-[[(l-Methyl-2-propyl-4(lH)-quinolinylidene)hydrazino]methyl]-[l,l '- biphenyl]-2-carboxylic acid 4) 4-[[(2-Butyl- l-methyl-4(lH)-quinolinylidene)hydrazino]sulfonyl]benzoic acid
5) 4'-[[(2-Ethyl-l-methyl-4(lH)-quinolinylidene)hydrazino]sulfonyl]-[l,l'- biphenyl]-2-carboxylic acid
6) Benzen-l,4-dicarboxylic acid, 4-(l-methyl-2-propyl-4(lH)- quinolinylidene)hydrazide
7) [l,l'-Biphenyl]-2,4'-dicaιboxylic acid, 4'-[l,2-dimethyl-4(lH)- quinolinylidene)hydrazide
8) 2-Ethyl-l-methyl-4(lH)-quinolinone, [2'-(lH-tetrazol-5-yl)[l,l '-biphenyl]-4- yl]hydrazone 9) l-Methyl-2-propyl-4(lH)-quinolinone, [[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4- yl]methyl]hydrazone
10) 2-Ethyl-l-methyl-4(lH)-quinolinone, [[2'-(lH-tetrazoI-5-yl)[l,l ' -biphenyl] -4- yl]sulfonyl]hydrazide
11) 4-[l,2,6-Trimethyl-4-(lH)-pyridinylidene)hydrazino]benzoic acid 12) 4-[l-Benzyl-2,6-dimethyl-4(lH)-pyridinylidene)hydrazino]benzoic acid
13) 4-[(2,6-Dimethyl-l-phenyl-4(lH)-pyridinylidene)hydrazino]benzoic acid
14) 3-[[(l,2,6-Trimethyl-4(lH)-pyridinylidene)hydrazino]sulfonyl]benzoic acid
15) 4'-[[(l,2,6-Trimethyl-4(lH)-pyridinylidene)hydrazino]sulfonyl]-[l,l'-biphenyl]-2- carboxylic acid 16) 4'-[[(l-Benzyl-2,6-dimethyl-4(lH)-pyridinylidene)hydrazino]sulfonyl]-
[1,1 'biphenyl] -2-carboxylic acid
17) 4-[[(4-Carboxyphenyl)sulfonyl]hydrazono]- 1 ,4-dihydro- 1 ,2,6-trimethyl-pyridine- 3-carboxylic acid
18) 4-[[(4-Carboxyphenyl)sulfonyl]hydrazono]- 1 ,4-dihydro- 1 ,2,6-trimethyI-3- pyridineacetic acid
19) [1,1 '-Biphenyl]-2,4'-dicarboxylic acid, 4'-(2,6-diethyl-l-methyl-4(lH)- pyridinylidene)hydrazide
20) 4'-[[(2,6-diethyl-l-methyl-4(lH)-pyridinylidene)hydrazino]methyl-[l,l'- biphenyl]-2-carboxylic acid 21) l,2,6-Trimethyl-4(lH)-pyridone, [[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4- yl ]sulfonyl] hydrazide
22) 2,6-Diethyl-l-methyl-4(lH)-pyridone, [[2'-(lH-tetrazol-5-yl)[l,l '-biphenyl]-4- yl]methyl]hydrazide
23) 4-(hexadecyloxy)-3-[[[2-(4-methoxy-m-tolyl)-l-methyl-6-sulfo-4(lH)- quinolylidene]hydra-zino]sulfonyl]-benzoic acid
24) 3-[[[2-(4-ethoxy-3-methoxyphenyl)- l-methyl-6-sulfo-4(lH)- quinolinylidene]hydrazino]-sulfonyl]-4-(hexadecyloxy)-benzoic acid
25) 1 ,4-dihydro- l-methyl-4-oxo-2-[p-(p-tolyloxy)phenyl]-6-quinolinesulfonic acid, (hexadecylsulfonyl)hydrazone
26) 3-[[[2-(p-carboxyphenyl)- l-methyl-6-sulfo-4(lH)- quinolylidene]hydrazino]sulfonyl]-4-(hexadecyloxy)-benzoic acid
27) 4-(hexadecyloxy)-3-[[[l-methyl-2-[p-(phenylsulfonyl)phenyl]-6-sulfo-4(lH)- quinolinylidene] -hydrazino] sulfonyl] -benzoic acid
28) 4-(hexadecyloxy)-3-[[( l-methyl-2-phenyl-6-sulfo-4(lH)- quinolylidene)hydrazino]sulfonyl] -benzoic acid 29) 4-(hexadecyloxy)-3-[[(l-methyl-6-sulfo-2-m-tolyl-4(lH)- quinolylidene)hydrazineo]sulfonyl]-benzoic acid
30) l,4-dihydro-l-methyl-4-oxo-2-phenyl-6-quinolinesulfonic acid, [[m- (hexadecylmethylsulfamoyl)phenyl]sulfonyl]-hydrazone
31) [p-[[[2-[p-(hexadecyloxy)phenyl]-l-methyl-6-sulfo-4(lH)- quinolinylidene]hydrazino]sulfonyl]phenoxy]-acetic acid
32) [6-acetamido- 1 -methyl-2-(p-sulfophenyl)-4( lH)-quinolyidene]hydrazide hexadecanesulfonic acid, sodium salt
33) 2-(3,4-dimethoxyphenyl)- 1 ,4-dihydro- 1 -methyl-4-oxo-6-quinolinesulfonic acid, (hexadecylsulfonyl)hydrazone 34) 5-[[[2-[p-(hexadecyloxy)phenyl]-l-methyl-6-sulfo-4(lH)- quinolylidene]hydrazino]sulfonyI]-salicylic acid
35) 4-[(hexadecylsulfonyl)-hydrazono]- l-methyl-2-phenyl-5-quinolinesulfonic acid
36) 2-(2-fluorophenyl)-4-[(hexadecylsulfonyl)hydrazono]-l,4-dihydro-l-methyl-6- quinolinesulfonic acid
PCT/US1993/008156 1992-10-06 1993-09-03 Use of 4-hydrazono-1,4-dihydro-pyridine and/or 4-hydrazino-pyridine derivatives for treatment of hypertension and congestive heart failure WO1994007492A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU50968/93A AU5096893A (en) 1992-10-06 1993-09-03 Use of 4-hydrazono-1,4-dihydro-pyridine and/or 4-hydrazino-pyridine derivatives for treatment of hypertension and congestive heart failure

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US95805392A 1992-10-06 1992-10-06
US07/958,053 1992-10-06

Publications (1)

Publication Number Publication Date
WO1994007492A1 true WO1994007492A1 (en) 1994-04-14

Family

ID=25500544

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/008156 WO1994007492A1 (en) 1992-10-06 1993-09-03 Use of 4-hydrazono-1,4-dihydro-pyridine and/or 4-hydrazino-pyridine derivatives for treatment of hypertension and congestive heart failure

Country Status (2)

Country Link
AU (1) AU5096893A (en)
WO (1) WO1994007492A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6352630B1 (en) * 1999-02-23 2002-03-05 Asulab S.A. Electrochemical system for determining blood coagulation time
US6638977B1 (en) 1999-11-19 2003-10-28 Corvas International, Inc. Plasminogen activator inhibitor antagonists
US6677473B1 (en) 1999-11-19 2004-01-13 Corvas International Inc Plasminogen activator inhibitor antagonists

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4980379A (en) * 1988-06-30 1990-12-25 The University Of Virginia Use of adenosine antagonists in the treatment of bradyarrhythmias and hemodynamic depression associated with cardiopulmonary resucitation and/or cardiovascular collapse

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4980379A (en) * 1988-06-30 1990-12-25 The University Of Virginia Use of adenosine antagonists in the treatment of bradyarrhythmias and hemodynamic depression associated with cardiopulmonary resucitation and/or cardiovascular collapse

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
G.C.WRIGHT ET AL.: "SYNTHESIS AND HYPOTENSIVE PROPERTIES OF NEW 4-AMINOQUINOLINES", J.MED.CHEM., vol. 14, no. 11, 1971, pages 1066 - 1066 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6352630B1 (en) * 1999-02-23 2002-03-05 Asulab S.A. Electrochemical system for determining blood coagulation time
US6638977B1 (en) 1999-11-19 2003-10-28 Corvas International, Inc. Plasminogen activator inhibitor antagonists
US6677473B1 (en) 1999-11-19 2004-01-13 Corvas International Inc Plasminogen activator inhibitor antagonists

Also Published As

Publication number Publication date
AU5096893A (en) 1994-04-26

Similar Documents

Publication Publication Date Title
JP2927519B2 (en) Substituted triazolinones, triazolinthiones and triazolinimines as angiotensin II antagonists
EP0555331B1 (en) N-substituted imidazol-2-one compounds for treatment of circulatory disorders
US4273782A (en) Inhibition of thromboxane synthetase by 3-(1-Imidazolylalkyl) indoles
JP3883205B2 (en) Treatment of Atherosclerosis with Angiotensin II Receptor Blocking Imidazole
US5164403A (en) N-arylheteroarylalkyl imidazol-2-one compounds for treatment of circulatory disorders
PT92935B (en) METHOD FOR PREPARING A PYRAZOLE-PYRIDINE COMPOUND AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT
WO2008156580A1 (en) Triazole derivatives for treating alzheimer's disease and related conditions
US6570013B2 (en) Salts of zopolrestat
CZ20002310A3 (en) Indole derivatives as inhibitors of Xa factor, process of their preparation and pharmaceutical composition in which they are comprised
Chakravarty et al. A highly potent, orally active imidazo [4, 5-b] pyridine biphenyl acylsulfonamide (MK-996; L-159,282): A new AT1-selective angiotensin II receptor antagonist
CA2154807A1 (en) Method of treating or preventing cardiac arrhythmia employing an n-substituted heterocyclic derivative
SK12462001A3 (en) Dihetero-substituted metalloprotease inhibitors
TW201016678A (en) Compounds, compositions and methods comprising imidazole and triazole derivatives
US5250558A (en) Substituted triazolinones, triazolinethiones, and triazolinimines as neurotensin antagonists used to treat psychosis
WO1994007492A1 (en) Use of 4-hydrazono-1,4-dihydro-pyridine and/or 4-hydrazino-pyridine derivatives for treatment of hypertension and congestive heart failure
SK15499A3 (en) Pharmaceutical products for curing and preventing illnesses connected with the malfunction of vascular endothelial cells
PT610698E (en) IMIDAZO (4,5-B) PYRIDINES AND BENZIMIDAZOLES SUBSTITUTED AS ANGUITENSIN II ANTAGONISTS
CZ2001126A3 (en) Coadministration of ACAT and MMP inhibitors for the treatment of atherosclerotic lesions
KR880002531B1 (en) 4,5-dihydro-6,(2 -(4-(1h-imidazol-1-yl) phenyl)-ethenyl)-3(2h)-pyridazinones and process for the preparation thereof
EP0732925A1 (en) A method of treating gastrointestinal motility disorders
PT1441723E (en) Use of irbesartan for the preparation of medicaments that are used to prevent or treat pulmonary hypertension
PT100698B (en) INDOLE COMPOUNDS SUBSTITUTED IN POSITION 3- (7-CARBONYL (PYRIDIN-3-YL) PYRROLE {1,2-C} THIAZOL, 7-CARBONYL (PYRIDIN-3-YL) PYRROLE (1,2-C) OXAZOLIN CARBONYL (PYRIDIN-3-IL) PYRROLE (1,2-C) PYRROL, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE
US6342505B1 (en) Use of 4-substituted tetrahydropyridines for making medicines acting on TGF-β1
WO1999036068A1 (en) Potassium channel activators
PT92147B (en) PROCESS FOR THE PREPARATION OF PYRROLIDINE DERIVATIVES

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR BY CA CH CZ DE DK ES FI GB HU JP KP KR KZ LK LU MG MN MW NL NO NZ PL PT RO RU SD SE SK UA US VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA