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WO1983000863A1 - 4-pyridylpyridazin(2h)-3-ones antiinflammatoires et analgesiques - Google Patents

4-pyridylpyridazin(2h)-3-ones antiinflammatoires et analgesiques Download PDF

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Publication number
WO1983000863A1
WO1983000863A1 PCT/US1982/001118 US8201118W WO8300863A1 WO 1983000863 A1 WO1983000863 A1 WO 1983000863A1 US 8201118 W US8201118 W US 8201118W WO 8300863 A1 WO8300863 A1 WO 8300863A1
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Prior art keywords
pyridyl
compound
hydroxyethyl
diphenylpyridazin
hydrochloride
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Ceased
Application number
PCT/US1982/001118
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English (en)
Inventor
Shamrock Corporation Diamond
Larry J. Powers
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Diamond Shamrock Corp
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Diamond Shamrock Corp
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Filing date
Publication date
Application filed by Diamond Shamrock Corp filed Critical Diamond Shamrock Corp
Publication of WO1983000863A1 publication Critical patent/WO1983000863A1/fr
Anticipated expiration legal-status Critical
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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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates generally to 4-pyridylpyridazinone derivatives which exhibit valuable antiinflammatory and analgesic activity in warm-blooded animals.
  • the invention also relates to novel pharmaceutical compositions containing active 4-pyridylpyridazinone compounds and their use for inducing or obtaining antiphlogistic and/or analgesic effects in mammals.
  • U.S. Patent No. 3,689,652 discloses 6-(substituted- phenyl)-4,5-dihydro-3(2H)-pyridazinones as hypotensive agents. More specifically, 6-halomethylphenyl-5-methyl (or unsubstituted)-4,5-dihydro-3(2H)- pyridazinone compounds are- disclosed. In related U.S. Patent Nos.
  • the patentees further disclose corresponding 6-substituted phenyl-4,5-d ⁇ hydro-pyridazinone compounds wherein the additional phenyl substituents include lower alkanoyl, nitro, amino, lower alkanoylamino and cyano wherein the 2- position of the pyridazinone ring may be optionally substituted by lower alkyl.
  • U.S. Patent No. 3,657,242 discloses a series of 4,5-dihydro-pyridazin- (2H)-3-one and hexahydropyridazines and, more specifically, certain 2-hydroxy- alkyl-6-aryl or heterocyclic substituted-4,5-dihydro-pyridazinones and hexa ⁇ hydropyridazines useful as antiinflammatories. • *
  • the foregoing compounds are representative of 4,5-dihydro- pyridazinone compounds previously suggested as pharmacologically active compounds.
  • the foregoing compounds comprise dihydro (saturated) ketopyridazines.
  • pyridaz-3-one compounds disclosed in U.S. Patent No. 2,839,532.
  • the aforesaid patent is directed to 4,5-u ⁇ saturated pyridaz-3-one (or 3-ketopyridazine) compounds having a cyano, acetyl, carboxyl, earbethoxy or benzoyl group in the 4- position optionally substituted in the 5,6- positions by lower alkyl, phenyl or substituted phenyl residues.
  • These compounds are disclosed as being useful as medicaments, particularly, analgesics, anesthetics, antibacterials or disinfectants.
  • analgesics, anesthetics, antibacterials or disinfectants u.S. Patent No. 3,491,096 and British Patent No.
  • 840,522 are directed to other previously investigated pyridazone compounds.
  • the aforementioned British patent pertains to 2-hydroxymethyl-6-phenyl-3-pyridazone and the analgesic utility thereof.
  • U.S. Patent No. 3,491,096 describes 2-pyridylalkyla.ted- 6-phenyl-pyridaz-3-one compounds possessing sedative, analgesic and antispas- modic properties, with occasional hypo tensive effects being observed.
  • novel 4-pyr ⁇ dylpyridazinone compounds which evidence effective antiinflam ⁇ matory and analgesic activity in warm-blooded animals.
  • a method is provided for the treatment of inflammation, swelling, fever and the like conditions in mammals by the administration of preselected dosages of active 4-pyridyl- pyridaz ⁇ none compounds or pharmaceutically acceptable salts thereof in suitable nontoxic pharmaceutical dosage unit forms or compositions.
  • novel, stable nontoxic pharmaceutical compositions and/or formulations adaptable for, e.g., oral, rectal, parenteral, etc., administration are provided.
  • novel class of compounds of the present invention are various 4- pyr ⁇ dylpyridazinone compounds of the general formula I below:
  • R is hydrogen, hydroxyalkyl or alkoxycarbonylalkyl
  • R. is 2-pyridyl, 3- pyridyl or 4-pyridyl
  • RRON and R are the same and represent phenyl, halophenyl or alkylphenyl.
  • alkyl and alkoxy are inclusive of straight and branched chain carbon-carbon linkages, e.g., methyl, ethyl, N-propyl, isopropyl, N-butyl, tert- butyl, etc., and represent 1 to 5 carbon atoms.
  • pharmaceutically acceptable nontoxic salts as used herein is intended to include those salts capable of being formed with the instant compounds and substituted derivatives thereof in accordance with the invention without materially altering the chemical structure or pharmacological properties of the parent compounds.
  • acids for reaction with sufficiently basic pyridazinone derivatives include hydrochloric, hydrobromic, hydroiodic, nitric, phosphoric, citric, etc.
  • Alkali metal salts of carboxylic acid derivatives of the invention may be obtained by reaction with suitable bases, e.g., sodium hydroxide, potassium hydroxide, etc. Alkaline earth metal salts may be similarly obtained.
  • keto compounds of the above formula wherein R, is hydrogen may be present in the enol tautomeric form. It is also noted that the other possible R, substituents, i.e., hydroxyalkyl and alkoxycarbonylalkyl, constitute possible enol ⁇ e derivatives and/or metabolites of compounds within the scope of the present invention.
  • the 4-pyridylpyr ⁇ daz ⁇ none i.e., substituted keto-pyridazine, compotmds of the present invention, may be prepared by various alternative methods heretofore employed in the synthesis of other pyridazinone compounds or modifications thereof to obtain the R., R,*, R restroom or , substituents thereon as defined above.
  • one method for the preparation of the 4-pyridylpyr ⁇ - dazinone compounds of the present invention comprises reacting an -appropriately substituted monohydrazone, with pyridyl acetic acid ethyl ester or reacting the appropriately substituted benzil and pyridyl substituted hydrazide under cyclization conditions, e.g., in the presence of suitable solvents, such as xylene ⁇ acetonitrile, methanol, benzene, etc., and alkaline condensing agents, such as hydroxides, alcoholates, hydrides, alkali or alkaline earth metals, tertiary amines, etc., to effect ring closure.
  • suitable solvents such as xylene ⁇ acetonitrile, methanol, benzene, etc.
  • alkaline condensing agents such as hydroxides, alcoholates, hydrides, alkali or alkaline earth metals, tertiary amines
  • the monohydrazone reactants may be prepared by the reaction of an appropriately substituted benzil with hydrazine hydrate.
  • Suitable benzil starting materials may be obtained commercially or prepared by known methods, for example, cyanide ion catalyzed benzoin condensation followed by oxidation.
  • the pyridazin(2H)-3-one compounds thus prepared may be utilized following recrystallization/pur ⁇ fication as an intermediate for the preparation of further 2-substituted derivatives in accordance with the above R, definition as illustrated more particularly in the specific examples of preferred embodiments of the invention hereinafter.
  • the compounds of the present invention evidence antiinflammatory and analgesic effects in warm-blooded animals. It will be appreciated, however, that the specific response elicited upon administration of the compounds of the present invention to an animal species in need thereof will vary depending upon the specific structure of the administered compound, the unit dose, dosage regimen and mode of administration, as well as the particular mammalian species involved. Accordingly, as detailed hereinbelow, certain of the compounds of the invention are preferred over others relative to a predetermined pharmacological activity.
  • Representative of preferred compounds of formula I for use in the analgesic compositions and methods of the present invention are 2-acetic acid-4- (4'-py ⁇ idyl)-5,6-diphenylpyridazin(2H)-3-one, ethyl ester; 4-(3 , -py ⁇ idyl)-5,6-bis(4 , - methylphenyl)pyridazin(2H)-3-one hydrochloride; 2-hydroxyethyl-4-(2 , -pyridyl)- 5,6-diphenylpyridazin(2H)-3-one hydrochloride; 4-(3 , -pyridyl)-5,6-diphenyl- pyridazin(2H)-3-one; and 4-(3'-pyridyl)-5,6-bis(4'-chlorophenyl)pyridazin(2H)-3- one.
  • especially preferred compounds falling within the aforesaid general formula I are 2-acetic acid-4-(4 , -pyridyl)-5,6-diphenylpyridaz ⁇ n(2H)-3-one, ethyl ester; 2-hydroxyethyl- 4-(2 , -pyridyl)-5,6-diphenylpyridazin(2H)-3-one hydrochloride; and 4-(3 ⁇ -pyridyl)- 5,6-diphenylpyridazin(2H)-3-one.
  • the active compounds of the invention may be administered alone or in combination with each other or administered in admixture with pharmaceutical diluents, carriers, excipients or adjuvants suitably selected with respect to the intended route of administration and conventional pharmaceutical practices.
  • pharmaceutical diluents, carriers, excipients or adjuvants suitably selected with respect to the intended route of administration and conventional pharmaceutical practices.
  • the active compound or compounds of the invention may be combined with such excipients as starch, lactose, sucrose, cellulose, magnesium stearate, and the like.
  • injectable dosage unit forms may be utilized to accomplish intraveneous, intramuscular or subcutaneous administration and, for such parenteral adminis ⁇ tration, suitable sterile aqueous or nonaqueous solutions or suspensions, optionally containing appropriate solutes to effectuate isotonieity, will be employed.
  • suitable sterile aqueous or nonaqueous solutions or suspensions optionally containing appropriate solutes to effectuate isotonieity.
  • suitable adjuvants and dosage forms will be apparent to those skilled in the art.
  • Compounds of the invention or compositions thereof may * be administered to warm-blooded animals, i.e., mammals, including, for instance, mice, rats, guinea pigs, dogs and other domesticated animals, or humans. .
  • Dosages sufficient to elicit the above-identified antiinflammatory and/or analgesic response will generally range between about 1 to about 500 mg/kg/day in laboratory mice based upon body weight, and preferably between about 10 to about 200 mg/kg/day.
  • the foregoing dosages will normally be administered in 3 or 4 divided doses, depending upon the desired dosage regimen.
  • the actual effective dosage to be administered will vary, depending upon the specific compound involved, as well as the age, weight and responsiveness of the particular species.
  • the compounds of the invention exhibit relatively low toxicities and the acute oral LD 50 (lethal dose to 50 percent of mice) will generally be greater than 300 mg/kg.
  • Example 2 The compound of Example 2 (9.0 g.) and ethylene carbonate 2.7 g. 0 were slurried in DMF (100 mL.) and 3 powdered KOH pellets added. The reactants were stirred at 110-120° for 2 hrs. The mixture was poured into water and the suspension extracted with benzene. The organic layer was washed with water and dried over Na 2 SO ,. HC1 gas was bubbled through the solution to give a gummy precipitate which solidified on addition of ether. The solid was separated and recrystallized from MeOH-EtOAc. Yield 7.2 g., M.P. 237-247° C, decomposition with effervescence.
  • Antiinflammatory activity i.e., effectiveness in the prevention and inhibition of granuloma tissue formation, is demonstrated by relative inhibition of carrageenin-induced edema as determined by the diminution of experimental edema induced in the hind paw of a rat by the injection of carrageenin.
  • the procedure employed is a modification of the method of Winter et al, Proc. Soc. Exptl. Biol. Med., 111:544 (1962).
  • the device used for measurement of the paw volume is an adaptation of the. water displacement procedure described by Adamkiewicz et al, Can. J. Biochem. Physiol., 33:332 (1955). Test compounds were administered orally, one hour prior to the intraplanter injection of 0.05 mL. of sterile 1.0% solution of carrageenin into the left hind paw of male rats (Long Evans strain) weighing between about 130-200 g. At peak swelling time (3 hrs.) the volume of edema was calculated by differential paw
  • Table I sets forth results obtained at the indicated dosages with representative compounds of the present invention.
  • Phenylquinone writhing test was employed to evaluate analgesic activity for selected compounds for the present invention according to the following procedure:
  • Phenylquinone (phenyl-p-benzoqu ⁇ none, No. 7104, Eastman Organic Chemicals) is made up as a 0.02% aque ⁇ us solution and 5% ethyl alcohol. Phenylquinone solutions are made up fresh twice daily. Standard reference agents and the test compounds are dissolved or suspended in a 0.25% methyl- cellulose solution. ' A control group consisting of 10 mice (Carworth CF. male mice) are administered the 0.02% phenylquinone solution at a dose of 0.25 mL./mouse. The mice are housed individually and observed closely for 10 min. for exhibition of writhing. The onset of writhing occurs within 3 min.
  • mice are administered orally to groups of 10 mice. The volume given is 0.01 mL. per gram of body weight. Activity can be studied at 15, 30, 60 and 120 min. after oral administration. After the designated time interval of a dose group has elapsed, the mice are challenged with phenylquinone intraperitoneally. "Complete blocking of the
  • the compounds of the present invention were further tested to determined if they exhibited adverse neurotoxic effects.
  • a standard testing procedure was employed to determine the mean neurotoxic dose in 50% of test mice.
  • the mean neurotoxic dose (expressed as NTD 5Q value in mg/kg) is defined as that dose of the drug administered orally or intraperitoneally (i.p.) to test mice that causes minimal recognizable neurotoxicity in 50% of the animals tested.
  • the procedure followed is described by Swinyard et al, J. Pharmac. Exp. Therap., 106, 319-330 (1952).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Nouvelles 4-pyridylpyridazinones de formule:$(10,)$s'étant révélées comme des agents anti-inflammatoires et analgésiques utiles.
PCT/US1982/001118 1981-09-11 1982-08-18 4-pyridylpyridazin(2h)-3-ones antiinflammatoires et analgesiques Ceased WO1983000863A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US30132881A 1981-09-11 1981-09-11
US301,328810911 1981-09-11

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WO1983000863A1 true WO1983000863A1 (fr) 1983-03-17

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EP (1) EP0088128A4 (fr)
JP (1) JPS58501432A (fr)
IL (1) IL66761A0 (fr)
IT (1) IT1149073B (fr)
WO (1) WO1983000863A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0714895A1 (fr) * 1994-12-01 1996-06-05 F. Hoffmann-La Roche AG Dérivés du pyrrole
WO1998041511A1 (fr) * 1997-03-14 1998-09-24 Merck Frosst Canada & Co. Pyridazinones utilises comme inhibiteurs de cyclo-oxygenase-2
US6004960A (en) * 1997-03-14 1999-12-21 Merck Frosst Canada, Inc. Pyridazinones as inhibitors of cyclooxygenase-2
EP1043317A4 (fr) * 1997-11-19 2003-03-05 Kowa Co Nouveaux derives de pyridazine et medicaments contenant ces composes comme principe actif

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB840522A (en) * 1957-11-05 1960-07-06 Lepetit Spa A new analgesic 2-hydroxymethyl-6-phenyl-3-pyridazone
US3658814A (en) * 1970-03-17 1972-04-25 Sandoz Ag 2-(omega-chloroalkyl)-6-aryl substituted-4 5-dihydropyridazin(2h)-3-one
US3920646A (en) * 1967-11-02 1975-11-18 Sandoz Ag 3-Substituted-1-pyridyl-1,4,5,6-tetrahydropyridazines
US3931176A (en) * 1970-11-12 1976-01-06 Sandoz Inc. Hydroxyalkyl substituted-4,5-dihydropyridazin(2H)-3-ones
JPS5143776A (en) * 1974-09-24 1976-04-14 Chemie Linz Ag 33 fuenirupiridazonkagobutsuno seiho
JPS5419987A (en) * 1977-07-15 1979-02-15 Yoshitomi Pharmaceut Ind Ltd Pyridazinone derivative and its preparation
US4238490A (en) * 1979-02-12 1980-12-09 Diamond Shamrock Corporation Antihypertensive pyridazin(2H)-3-ones
US4280998A (en) * 1978-08-08 1981-07-28 Bayer Aktiengesellschaft 1,4-Dihydropyridazine-3-carboxylic acid derivatives, a process for their preparation and their use as antihypertensives
US4298609A (en) * 1979-08-30 1981-11-03 Sterling Drug Inc. 4,5-Dihydro-6-(4-pyridinyl)-3-pyridazinol and salts, their preparation and use as blood pressure lowering agents

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB840522A (en) * 1957-11-05 1960-07-06 Lepetit Spa A new analgesic 2-hydroxymethyl-6-phenyl-3-pyridazone
US3920646A (en) * 1967-11-02 1975-11-18 Sandoz Ag 3-Substituted-1-pyridyl-1,4,5,6-tetrahydropyridazines
US3658814A (en) * 1970-03-17 1972-04-25 Sandoz Ag 2-(omega-chloroalkyl)-6-aryl substituted-4 5-dihydropyridazin(2h)-3-one
US3931176A (en) * 1970-11-12 1976-01-06 Sandoz Inc. Hydroxyalkyl substituted-4,5-dihydropyridazin(2H)-3-ones
JPS5143776A (en) * 1974-09-24 1976-04-14 Chemie Linz Ag 33 fuenirupiridazonkagobutsuno seiho
JPS5419987A (en) * 1977-07-15 1979-02-15 Yoshitomi Pharmaceut Ind Ltd Pyridazinone derivative and its preparation
US4280998A (en) * 1978-08-08 1981-07-28 Bayer Aktiengesellschaft 1,4-Dihydropyridazine-3-carboxylic acid derivatives, a process for their preparation and their use as antihypertensives
US4238490A (en) * 1979-02-12 1980-12-09 Diamond Shamrock Corporation Antihypertensive pyridazin(2H)-3-ones
US4298609A (en) * 1979-08-30 1981-11-03 Sterling Drug Inc. 4,5-Dihydro-6-(4-pyridinyl)-3-pyridazinol and salts, their preparation and use as blood pressure lowering agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
European J. Med. Chem. issued February 1979, NANNINI et al, Synthesis and Pharmacological Activity of some 5,6-Diphenyl-Pyridazines, pp 53-60 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0714895A1 (fr) * 1994-12-01 1996-06-05 F. Hoffmann-La Roche AG Dérivés du pyrrole
US5622948A (en) * 1994-12-01 1997-04-22 Syntex (U.S.A.) Inc. Pyrrole pyridazine and pyridazinone anti-inflammatory agents
WO1998041511A1 (fr) * 1997-03-14 1998-09-24 Merck Frosst Canada & Co. Pyridazinones utilises comme inhibiteurs de cyclo-oxygenase-2
US6004960A (en) * 1997-03-14 1999-12-21 Merck Frosst Canada, Inc. Pyridazinones as inhibitors of cyclooxygenase-2
EP1043317A4 (fr) * 1997-11-19 2003-03-05 Kowa Co Nouveaux derives de pyridazine et medicaments contenant ces composes comme principe actif
EP2017266A1 (fr) * 1997-11-19 2009-01-21 Kowa Co., Ltd. Dérivés de pyridazine et medicaments les contenant comme principe actif

Also Published As

Publication number Publication date
EP0088128A1 (fr) 1983-09-14
EP0088128A4 (fr) 1984-04-06
IT1149073B (it) 1986-12-03
IL66761A0 (en) 1982-12-31
IT8249095A0 (it) 1982-09-09
JPS58501432A (ja) 1983-08-25

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