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WO1989008108A1 - Composes de pyridyl-pyridazinone et de pyridyl-pyrazolinone et leur utilisation dans le traitement d'arret cardiaque congestif - Google Patents

Composes de pyridyl-pyridazinone et de pyridyl-pyrazolinone et leur utilisation dans le traitement d'arret cardiaque congestif Download PDF

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Publication number
WO1989008108A1
WO1989008108A1 PCT/US1988/000666 US8800666W WO8908108A1 WO 1989008108 A1 WO1989008108 A1 WO 1989008108A1 US 8800666 W US8800666 W US 8800666W WO 8908108 A1 WO8908108 A1 WO 8908108A1
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WIPO (PCT)
Prior art keywords
compound according
hydrogen
pyridyl
alkyl
imidazol
Prior art date
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PCT/US1988/000666
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English (en)
Inventor
Donald E. Kuhla
Henry F. Campbell
William L. Studt
William C. Faith
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Rorer International (Overseas) Inc.
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 Rorer International (Overseas) Inc. filed Critical Rorer International (Overseas) Inc.
Priority to PCT/US1988/000666 priority Critical patent/WO1989008108A1/fr
Publication of WO1989008108A1 publication Critical patent/WO1989008108A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • This invention relates to pyridazinone and pyrazolinone compounds useful as cardiotonic agents for the treatment of congestive heart failure, to their preparation and to pharmaceutical compositions including the same.
  • Congestive heart failure is a life threatening condition in which myocardial contractility is depressed such that the heart is unable to adequately pump the blood returning to it.
  • Normal pathologic sequelae include decreased cardiac output, venous pooling, increased venous pressure, edema, increased heart size, increased myocardial wall tension, and eventually cessation of contractility.
  • Digitalis glycosides have long been used to increase myocardial contractility and reverse the detrimental changes seen in congestive heart failure. More recently, dopamine, dobutamine, and amrinone have been used to provide necessary inotropic support for the failing heart.
  • inotropic drugs include the substituted pyridazinones disclosed in U.S. Patent No. 4,353,905, wherein the 6-position of the pyridazinone is substituted by 4-imidazolyl phenyl, and in U.S. Patent Nos. 4,397,854 and 4,404,203, where the 6-position of the pyridazinone is substituted by various substituted phenyl groups.
  • the present invention relates to a class of novel pyridazinone and pyrazolinone compounds which exhibit cardiotonic activity in humans and mammals .
  • This invention relates to the compounds described by the Formula I
  • Het is imidazol-1-yl or 1,2,4-triazol-1-yl; py is 2-, 3-or 4-pyridyl x is 0 or 1;
  • R n is hydrogen, alkyl, aralkyl, acyl, carbalkoxy, carbamyl, carbalkoxyalkyl, hydroxyalkyl, alkoxyalkyl or amidino;
  • R 1 and R 2 are each independently hydrogen, alkyl or aralkyl
  • R is hydrogen or
  • Y is hydrogen, -O-R a ,
  • R ⁇ is hydrogen, alkyl or acyl and
  • R ⁇ is hydrogen or alkyl
  • R ⁇ and R ⁇ together may form a 3-7 membered ring which may also contain 0-2 additional hetero atoms selected from N, O and S; or a pharmaceutically acceptable salt thereof.
  • This invention also relates to pharmaceutical compositions for use in increasing cardiac contractility in humans and to the uses of these compounds in the treatment of congestive heart failure in humans and other mammals.
  • R and R n are as described above and X is CH or N.
  • Alkyl means a saturated aliphatic chain, either branched or straight, including up to about 6 carbon atoms.
  • “Lower alkyl” means an alkyl group as above, having 1 to about 4 carbon atoms. Examples of lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
  • “Aralkyl” means an alkyl group substituted by an aryl radical. The preferred aralkyl groups are benzyl or phenethyl .
  • acyl means an organic radical derived from an organic acid by the removal of its hydroxyl group.
  • Preferred acyl groups are acetyl, propionyl, benzoyl, etc.
  • Alkoxy refers to a loweralkyl-O- group.
  • halo means a halogen.
  • Preferred halogens include chloride, bromide, and fluoride.
  • 2-pyridyl means a pyridyl ring bonded to the pyridazinone or pyrazolinone ring described in Formula I at the pyridyl carbon ortho to the nitrogen atom.
  • 3-pyridyl means a pyridyl ring bonded to the pyridazinone or pyrazolinone ring described in Formula I at the pyridyl carbon meta to the nitrogen atom.
  • 4-pyridyl means a pyridyl ring bonded to the pyridazinone or pyrazolinone ring described in Formula I at the pyridyl carbon para to the nitrogen atom.
  • Het means imidazol-1-yl or 1,2,4-triazol-1-yl.
  • the compounds of this invention may be useful in the form of the free base, if a basic group is present, in the form of salts and as a hydrate, and all forms are within the scope of the invention.
  • Acid addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the base form.
  • the acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial cardiotonic properties inherent in the free base are not vitiated by side effects ascribable to the anions.
  • Pharmaceutically acceptable salts within the scope of the invention are those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like.
  • mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid
  • organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic
  • the corresponding acid addition salts comprise the following: hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartarate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.
  • the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • the 3-pyridyl compounds of Formula I may be prepared from the morpholino cyano intermediate, Formula IV below, according to the reaction sequences shown in Schemes I and II below.
  • the 2- and 4-pyridyl compounds of Formula I may be prepared using the analogous 2- and 4-pyridyl intermediates.
  • the anion of intermediate IV may be alkylated with an alkyl ester of a haloacetic acid and the resulting alkylation product V treated with hydrazine affording the cyclized end product, as shown in Scheme I above.
  • the 6-membered ring may be prepared by reacting the anion of intermediate IV with the ester of an alpha, beta-unsaturated carboxylic acid, thereby forming the 1,4-addition product VI. Reaction of the addition product with a hydrazine forms the cyclized end product, as shown in Scheme II below.
  • the anion of the intermediate IV may be prepared using a strong base in an aprotic polar solvent such as THF or DMF.
  • the base may be the lithium anion of diisopropyl amine in THF, sodium methoxide in THF or sodium hydride in DMF.
  • the intermediate IV may be prepared according to the reaction sequence depicted in Scheme III below.
  • 2-Halo nicotinic acid methyl ester may be treated with imidazole and sodium hydride affording the 2-imidazol ⁇ l derivative.
  • the ester functionality is reduced to the alcohol followed by oxidation to the aldehyde.
  • the resulting 2-imidazolyl-5-formyl pyridine is refluxed with p-toluene sulfonic acid and morpholine in THF followed by treatment with potassium cyanide.
  • the cyano morpholino intermediate IV results.
  • the corresponding thio -S-R compound can be prepared by conversion of hydroxymethyl intermediate into the corresponding mesylate, followed by treatment of the latter with a thiol and DBU in benzene. Treatment of the resulting sulfide with a hydrazine produces the thiomethyl derivative of Formula I. This is described below.
  • a solution of the methyl ester obtained in Step 1. above (16.29 g) in DMF is added dropwise to a DMF suspension of sodium imidazole [prepared from NaH (4.19 g) and imidazole 6.49 g)] at RT.
  • the reaction mixture is heated to 120°C for nineteen hours.
  • the cooled reaction mixture is partitioned between water and chloroform, the organic layer separated, washed with water, dried over Na 2 SO 4 , filtered, evaporated, and residual DMF removed under high vacuum yielding the desired product as a tan solid which is recrystalized from methanol (M.P. 183-184.5oC) before use in the next step.
  • NaBH. (37.82 g) is added portionwise to a suspension of the imidazolyl ester of Step 2. above (9.98 g) in methanol at about 0.°C.
  • the reaction mixture is heated to reflux for 7 1/2 hours, allowed to cool and stand 15 hours.
  • MnO 2 (18.17 g) is added to a solution of the hydroxy methyl compound of Step 3. above (6.1 g) in CHCl 3 , and the resulting reaction mixture heated to reflux for 22 hours, allowed to cool, filtered, and the organic layer evaporated affording the desired product as a white solid used in the next step without further purification.
  • M.P. 139.5-140.5°C.
  • the formyl compound of Step 4 above (5.0 g) is added to a solution of pTSA monohydrate (5.95 g), THF (30.0 ml) and morpholine (5.44 g).
  • the reaction mixture is heated to reflux for 2 hours, cooled and a solution cf KCN (2.54 g) in water (4.5 ml) added. Refluxing is continued overnight, after which the reaction mixture is cooled and partitioned between water and chloroform.
  • the chloroform extract is washed with aqueous sodium bisulfite, brine, dried over Na 2 SO 4 , filtered and evaporated affording the desired product as a yellow solid used in the next step without further purification.
  • Step 7 4,5-dihydro-6-[6-(1H-imidazol-1-yl)pyrid-3-yl]- 5-methyl-3(2H)-pyridazinone
  • Potassium hydroxide (0.18 g) is added to a stirring solution of ⁇ -cyano-6-(1H-imidazol-1-yl)- ⁇ -morpholino-3- picoline (3.0 g) in anhydrous THF (120 ml).
  • the reaction mixture is stirred for 10 minutes and ethyl acrylate (6.03 g) is added to the mixture. Stirring is continued for 2 hours at RT after which a second portion of KOH (0.18 g in 0.5 ml ethanol) and ethyl acrylate 6.03 g) is added.
  • Step 2. 4 5-dihydro-6-[6-(1H-imidazol-1-yl)pyrid-3-yl]-3- (2H)-pyridazinone
  • Hydrazine monohydrate (0.41 g) is added to a stirred solution of the product obtained in Step 1. above (2.5 g) in ethanol (50 ml) and the reaction mixture refluxed for 67 hours. A second portion of hydrazine monohydrate (0.41 g) is added to the refluxing reaction mixture and refluxing continued for an additional 4 hours. The cooled mixture is concentrated, and suspended in methanol. Silica gel (8 g; 250-400 mesh) is added and the resulting suspension is concentrated in vacuo. The silica gel residue is stirred in anhydrous ether, concentrated in vacuo, layered onto a silica gel column, and eluted with a mixture of methanol: ethyl acetate (5:95).
  • the reaction mixture is poured into ice, the organic layer extracted with CHCl 3 , the chloroform extract washed with brine, dried over Na 2 SO 4 , filtered, evaporated, and the DMF removed under high vacuum, affording an oil.
  • the oil is chromotographed (silica gel), eluting fractions with a mixture of ethyl acetate: methanol (98:2), and the faster purified fractions combined to afford the desired product which is used in the next step without further purification.
  • the compounds of Formula I possess positive inotropic activity and are useful as cardiotonic agents in the treatment of humans and other mammals for cardiac disorders including congestive heart failure.
  • the effectiveness of the compounds of this invention as inotropic agents may be determined by the following pharmacologic tests which evaluate the change in cardiac contractile force upon exposure to a dose of said compounds.
  • the anesthetized dog procedure is a standard test procedure; the inotropic results of this procedure generally correlate with the inotropic activity found in human patients.
  • Female mongrel dogs (18.0 - 18.5 kg) are anesthetized with sodium pentobarbital (35 mg/kg i.v., supplemented as necessary during surgery) intubated and connected to a Harvard respirator.
  • the left side of the chest is opened at the fifth intercostal space, and a Konigsberg transducer inserted into the left ventricle through a puncture at the apex and secured.
  • a fluid-filled polyethylene catheter is inserted into the left atrium through a puncture wound and secured for measurement of left atrial pressure.
  • a second fluid-filled catheter is inserted into the aorta for measurement of blood pressure and heart rate and secured to the vessel wall.
  • the two catheters and the Konigsberg transducer cable are passed out of the chest through the seventh intercostal space and advanced subcutaneously to the back of the neck and passed through the skin.
  • the fluid-filled catheters are filled with heparnized 50% dextrose solution, and the chest is closed and evacuated.
  • the dogs are treated daily post-operatively with 600,000 units of penicillin-procaine i.m. for ten days and with chloramphenicol, 500 mg/kg i.m., every other day for 10 days and allowed at least 7 days recovery before use.
  • the dogs are fasted overnight before either intravenous or oral administration of the compound.
  • the dog On a test day, the dog is placed in a sling and connected to a recorder (Gould Instruments or Grass Instruments) for measurement of left ventricular pressure, left ventricular end diastolic pressure, left ventriuclar dP/dt max , blood pressure, heart rate (from the blood pressure signal), and the lead II electrocardiogram.
  • the compound is administered both intravenously and orally (liquid and soft gelatin capsule forms) in different experiments and blood samples were taken for determination of blood levels of the compound.
  • Guinea pigs are stunned by a sudden blow to the head; their chests are opened and hearts excised and placed in Kreb's medium (concentrations, mM: NaCl, 118.39; KCl, 4.70; MgSO 4 , 1.18; KH 2 PO 4 , 1.18; NaHCO 3 ; 25.00; glucose, 11.66; and CaCl 2 , 1.25 ⁇ gassed with a mixture of 95% O 2 5% CO 2 .
  • Left atria are removed and inserted into warmed 33oC double jacketed tissue chambers containing oxygenated Kreb's medium (as above). The upper end of each tissue is attached to a Statham Universal Transducing Cell via a Statham Microscale Accessory. Resting tension on each tissue is set at 1 g and adjusted periodically.
  • Massive field stimulation is achieved via a pair of platinum or silver electrodes placed on opposite sides of the tissue. Electrodes are made from 20 gauge silver wire wound into a tight coil approximately 12-14 mm in diameter. Electrodes are connected to a Grass stimulator via Grass constant current unit. Tissues are driven at 90 pulses per minute with a 5 msec duration at current levels 20% greater than threshold for continuous beat.
  • the compounds of this invention can be normally administered orally or parenterally, in the treatment of cardiac disorders such as heart failure in humans or other mammals .
  • compositions containing at least one compound according to the invention adapted for use in human or veterinary medicine.
  • Such compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. Suitable carriers include diluents or fillers, sterile aqueous media and various non-toxic organic solvents.
  • Suitable carriers include diluents or fillers, sterile aqueous media and various non-toxic organic solvents.
  • the compositions may be formulated in the form of tablets.
  • the particular carrier and the ratio of inotropic active compound to carrier are determined by the solubility and chemical properties of the compounds, the particular mode of administration and standard pharmaceutical practice.
  • excipients such as lactose, sodium citrate, calcium carbonate and dicalcium phosphate and various disintegrants such as starch, alginic acid and certain complex silicates, together with lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc, can be used in producing tablets.
  • lactose and high molecular weight polyethylene glycols are among the preferred pharmaceutically acceptable carriers.
  • the carrier can be emulsifying or suspending agents. Diluents such as ethanol, propylene glycol, glycerin and chloroform and their combinations can be employed as well as other materials.
  • solutions or suspensions of these compounds in sesame or peanut oil cr aqueous propylene glycol solutions, as well as sterile aqueous solutions of the soluble pharmaceutically acceptable salts described herein can be employed.
  • Solutions of the salts of these compounds are especially suited for intramuscular and subcutaneous injection purposes.
  • the acqueous solutions, including those of the salts dissolved in pure distilled water, are also useful for intravenous injection purposes, provided that their pH is properly adjusted, suitably buffered, made isotonic with sufficient saline or glucose and sterilized by heating or by microfiltration.
  • the dosage regimen in carrying out the methods of this invention is that which insures maximum therapeutic response until improvement is obtained and thereafter the minimum effective level which gives relief.
  • the dosages are those that are therapeutically effective in increasing the contractile force of the heart or in the treatment of cardiac failure.
  • the oral dose may be between about 0.01 mg/kg and about 50 mg/kg (preferably in the range of 0.1 to 10 mg/kg), and the i.v. dose about 0.005 to about 30 mg/kg (preferably in the range of 0.01 to 3 mg/kg), bearing in mind, of course, that in selecting the appropriate dosage in any specific case, consideration must be given to the patient's weight, general health, age, and other factors which may influence response to the drug.
  • the drug may be administered orally 1 to 4 times per day, preferably twice daily.

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  • Organic Chemistry (AREA)
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Abstract

L'invention se rapporte à des composés de pyridyl-pyridazinone et de pyridyl-pyrazolinone, à l'utilisation desdits composés comprenant des méthodes permettant d'accroître la contractilité cardiaque dans le traitement d'arrêt cardiaque congestif, ainsi qu'à des compositions pharmaceutiques renfermant ces composés, et à des procédés de préparation de ces compositions.
PCT/US1988/000666 1988-02-23 1988-02-23 Composes de pyridyl-pyridazinone et de pyridyl-pyrazolinone et leur utilisation dans le traitement d'arret cardiaque congestif WO1989008108A1 (fr)

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PCT/US1988/000666 WO1989008108A1 (fr) 1988-02-23 1988-02-23 Composes de pyridyl-pyridazinone et de pyridyl-pyrazolinone et leur utilisation dans le traitement d'arret cardiaque congestif

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PCT/US1988/000666 WO1989008108A1 (fr) 1988-02-23 1988-02-23 Composes de pyridyl-pyridazinone et de pyridyl-pyrazolinone et leur utilisation dans le traitement d'arret cardiaque congestif

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102008001932A1 (de) 2008-05-21 2009-11-26 Bayer Cropscience Ag Substiuierte Spiroisoxazoline
US10208024B2 (en) 2015-10-23 2019-02-19 Array Biopharma Inc. 2-aryl- and 2-heteroaryl-substituted 2-pyridazin-3(2H)-one compounds as inhibitors of FGFR tyrosine kinases
US12180207B2 (en) 2018-12-19 2024-12-31 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of FGFR tyrosine kinases

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4353905A (en) * 1981-09-17 1982-10-12 Warner-Lambert Company Substituted 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones and 6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones
US4521416A (en) * 1983-03-22 1985-06-04 Warner-Lambert Company 4,5-Dihydro-6-[(substituted)-1H-imidazol-4-yl or 5-yl]-3(2H)-pyridazinones and 6-[(substituted)-1H-imidazol-4-yl or 5-yl]-3(2H)-pyridazinones

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4353905A (en) * 1981-09-17 1982-10-12 Warner-Lambert Company Substituted 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones and 6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones
US4521416A (en) * 1983-03-22 1985-06-04 Warner-Lambert Company 4,5-Dihydro-6-[(substituted)-1H-imidazol-4-yl or 5-yl]-3(2H)-pyridazinones and 6-[(substituted)-1H-imidazol-4-yl or 5-yl]-3(2H)-pyridazinones

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102008001932A1 (de) 2008-05-21 2009-11-26 Bayer Cropscience Ag Substiuierte Spiroisoxazoline
US10208024B2 (en) 2015-10-23 2019-02-19 Array Biopharma Inc. 2-aryl- and 2-heteroaryl-substituted 2-pyridazin-3(2H)-one compounds as inhibitors of FGFR tyrosine kinases
US12180207B2 (en) 2018-12-19 2024-12-31 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of FGFR tyrosine kinases

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