NZ196844A

NZ196844A - 4-substituted-6-pyrid-(3 or 4)-ylpyridazin-3(2h)-ones

Info

Publication number: NZ196844A
Application number: NZ196844A
Authority: NZ
Inventors: G Y Lesher; W B Dickinson; B Singh
Original assignee: Sterling Drug Inc
Priority date: 1980-04-28
Filing date: 1981-04-16
Publication date: 1984-04-27
Also published as: ES501665A0; GB2075500B; GB2075500A; PT72935A; FI811304L; LU83322A1; AU6972481A; IT8121385A0; ES8301964A1; NO811420L; PT72935B; NL8102077A; IT1137568B; DE3116861A1; AR230279A1; FR2481284A1; DK186681A; SE8102660L; IL62675A0

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 1 96844 1 /r Q) V o o ■M-v-So* i • r 9 • I i I i i i • i ■ i i - - Priority * Corapk-to S^GDiJiSGtion FHod: ik'.H:V. Class:C-Pfty-01}. AM*31 l5f>. .., iW,c^ 27 APR 1984 i Vvwub^;.-^ ;< u~' ^T. £$ .O .s r - IA5 7 vs., ra*> jta ^ ^ f?5 ^ rS. U \a& ui# itf -sj iT& No.: Date: NEW ZEALAND PATENTS ACT, J 953 ^ 16 APR ^ I COMPLETE SPECIFICATION "6-(PYRIDINYL)-4-SUBSTITUTED-3(2H)-PYRIDAZINONES, USEFUL AS CARDIOTONIC AGENTS, AND PREPARATION" WWe; STERLING DRUG INC., a corporation organised under the laws of the State of Delaware, United States of America, of 90 Park Avenue, New York, State of New York, United States of America, hereby declare the invention for which ic/ we pray that a patent may be granted to owe/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (followed by page la) 4 -1^ ' I 968 4 4 5 10 15 20 f- N Iff—— . This invention relates to 6-(pyridinyl)-4-sub-stituted-3(2H)-pyridazinones, useful as cardiotonic agents, to their preparation, and to their use as cardiotonic agents. Haginiwa et al. [Yakugaku Zasshi 98_ (1), 67-71 (1978); Chem. Abstrs. 8_8, 170, 096v (1978)] reacted 3(2H)-pyridazinone with pyridine 1-oxide and platinized Pd-C catalyst to produce 6-(2-pyridinyl)-3(2H)-pyridazinone. Yoshitomi Pharmaceutical Ind., Ltd. Japanese Patent Application Disclosure No. 19,987/79 (available on request) , published February 15, 1979 and based on implication No. 85,192/77 filed July 15, 1977, discloses, inter alia, the preparation of 4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone by refluxing for two hours an ethanolic solution of 3-(iso-nicotinoyl)propanoic acid [same as y-oxo-y-(4-pyridinyl) butyric acid] and hydrazine hydrate. 4,5-Dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone and closely related 4,5-dihydro-6-(4- or 3- or 2-pyridinyl)-5-R-3(2H)-pyridazinones, where R is H or lower alkyl, are said (page 2 of English translation) to be "useful not only as medicines such as hypotensive and antithrombus agents because they have pharmacological actions such as hypotensive, blood platelet (5ft eg 196844 -2- coaguiation-inhibitory and membrane-stabilizing actions, but also as intermediates for the synthesis of such medicines". The present invention resides' in the 2-R-4-R'-6-PY-3(2H)-pyridazinones having Formula I or acid-addition salts thereof, where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, R is hydrogen, lower-alkyl or lower-hydroxyalkyl, and R1 is amino, carbamyl, carboxy, aminocarbamyl or lower-carbalkoxy, The compounds of Formula I where- R" is —NH2 (amino) and said salts are useful as cardiotonic agents, as determined by standard cardiotonic evaluation procedures„ Preferred embodiments are those where R1 is amino, PY is 4-pyridinyl or 3-pyridinyl and R is hydrogen, methyl, ethyl or 2-hydroxy-ethyl. Also other compounds of Formula I except those where R' is carboxy or those where R1 is lower-carbalkoxy when R is hydrogen are similarly useful as cardiotonic agents; the compounds of Formula I where R1 is carboxy or where R' is lower-carbalkoxy when R is hydrogen are useful as intermediates, e.g., in preparing the corresponding compounds where R' is carbamyl. Also, the compounds where R1 are carbamyl or aminocarbamyl are useful as intermediates in preparing the compounds of I R i )' -3- Formula I where Rs is amino. Preferred embodiments of Formula I where R' is other than amino are those where R is hydrogen, methyl or ethyl, Rf is carbamyl or aminocarbamyl and PY^is 4-pyridinyl or 3-pyridinyl. The compounds of Formula I where R is hydrogen may exist in tautomeric forms, that is, as 4-R'-6-PY-3(2H)-pyridazinones of Formula I and/or as 4-R'-6-PY-3-pyrida-zinols of Formula IA, illustrated as follows I IA 10 Structural preferences for known 3(2H)-pyridazinones or 3-pyridazinols would indicate the above Formula I to be the preferred tautomeric structure; thus, we have preferred to use the names based on structure I, although it is understood that either or both structures are comprehended 15 herein. One can react a di-(lower-alkyl) hydroxy [ 2-oxo-2-PY-ethyl]propanedioate (II) with a hydrazine salt of the formula RNHNH„.nH An (III) to produce lower-alkyl 2,3- x dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate (la:I where 20 R1 is lower-carbalkoxy). One can react la with hydrazine hydrate or anhydrous hydrazine to produce 2,3-dihydro-2- - --R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide (Ib:I —- where R' is aminocarbamyl), where PY and R are defined as 2 t APR 1985 EEG0V®3 196844 -4- above for Formula I, preferably 4-pyridinyl and hydrogen or methyl, respectively, n is 1 or 2, x is 1, 2 or 3, and An is an anion of a strong inorganic acid or an organic sulfonic acid. oxo-6-PY-4-pyridazinecarboxylate (la) to 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxamide (Ic:I where R' is carbamyl) either directly by reaction with ammonia or via the corresponding 2,3-dihydro-2-R-3-oxo-6-PY-4-10 pyridazinecarboxylic acid (Id:I where R' is carboxy) by hydrolyzing the ester to acid, reacting the acid with a chlorinating agent to form the acid chloride and reacting the latter with ammonia to form said carboxamide (Ic where R' is carbamyl), where R and PY have the meanings given 15 above for Formula I, preferably hydrogen or methyl and 4-pyridinyl, respectively. where R' is amino) by reacting a 2-R-6-PY-3(2H)-pyridazinone with hydrazine. One can also react a 2,3-dihydna-2-I<-3-oxD-20 6-PY-4-pyridazinecarboxamide (Ic) with a reagent capable of converting carbamyl to amino to produce 4-amino-2-R-6-PY-3 (2H) -pyridazinone (Ie) or react a 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide (lb) with a reagent capable of converting carboxylic acid hydrazide to amino, 25 where R and PY have the meanings given above for the compounds of Formula I. The conversion of Ic to Ie is pre- 5 One can convert a lower-alkyl ■ 2 , 3-dihydro-2-R-3- One can prepare the compounds of Formula Ie (I ed out using an aqueous alkali metal hypohalite, hypobromite or hypochlorite. The conversion of 196844 -5- Ib to Ie is preferably carried out using nitrous acid. Another aspect of the invention resides in the di-(lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioates of Formula II 0 -n2 it COOR PY-C-CH„-C-OH II JOOR1 or an acid-addition salt thereof where PY is defined as above for Formula I, preferably 4-pyridinyl, or 3-pyridinyl and is lower-alkyl, preferably ethyl or methyl,, One can react an acetylpyridine , of the formula 10 PY-GOCH-j (IV) with a di-(lower-alkyl) oxomalonate to produce a di-(lower-alkyl) , hydroxy [ 2-oxo-2-PY-ethyl ] propanedioate (II) where PY is defined as in Formula I above, preferably 4-pyridinyl. A cardiotonic composition for increasing cardiac3 15 contractility comprises a pharmaceutically-acceptable inert carrier and, as the active component thereof, an effective amount of a cardiotonic 2-R-4-R'-6-PY-3(2H)-pyridazinone of Formula I, that is, where R' is amino, carbamyl, aminocarbamyl or lower-carbalkoxy, R is hydrogen, lower-alkyl 20 or lower-hydroxyalkyl but is only lower-alkyl or lower- hydroxyalkyl when R' is lower-carbalkoxy, and PY is defined as in Formula I or a pharmaceutically-acceptable acid-addition salt thereof. Preferred such cardiotonic compounds are those where PY is 4-pyridinyl or 3-pyridinyl. 25 For increasing cardiac contractility in a patient ) 4 uiring such treatment one administers orally or ■>1CSVED 196844 -6- parenterally in a solid or liquid dosage form to such patient an effective amount of a cardiotonic 2-R-4-R' - 6-PY-3(2H)-pyridazinone or pharmaceutically-acceptable acid-addition salt thereof as defined above, where R1 is amino, carbamyl, 5 aminocarbamyl or lower-carbalkoxy. The term "lower alkyl" as used herein, e.g., as one of the meanings for R"(Formulas I, la, lb, Ic, Id, Ie or III) , the meaning for R-^ (Formula II) or as a substituent for PY (Formula I, la, lb, Ic, Id, Ie or II) means alkyl radicals having from one to six carbon atoms which 10 can be arranged as straight or branched chains, illustrated by methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl,and isobutyl. The symbol PY as used here, e.g„, as the 6-sub-stituent in the compounds having Formulas I, la, lb, Ic, Id, 15 Ie or II, means 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two "lower-alkyl" substituents, illustrated by 2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (alternatively named 2-methyl-5-pyridinyl), 2,3-dimethyl-4-20 pyridinyl, . 2-ethyl-4-pyridinyl, 2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridinyl, 2-n-hexyl-4-pyridinyl, 2,6-diethyl-4-pyridinyl, 2,6-diethyl-3-pyridinyl, 2, 6-diisopropyl-4-pyridinyl, 2,6-di-n-hexyl-4-pyridinyl, and the like. N.Z. PATENT OFF ICE 2 9 JUL 1983 received -7- The term "lower-hydroxyalkyl", as used herein, e.g., as one of the meanings for R in formulas I, la, lb, Ic, Id, Ie or III, means hydroxyalkyl radicals having form two to six carbon atoms and having its hydroxy group and its free valence bond (or connecting linkage) on different carbon atoms which can be arranged as straight or branched chains, illustrated by 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-hydroxy-l,1-dimethylethyl, 4-rhydroxybutyl, 5-hydroxyamyl, 6-hydroxy-hexyl, ah£ the like. The term "lower-carbalkoxy", as used herein, as one of the meanings for R* in formulas I and la, means carbalkoxy radicals where the alkoxy portion can be straight or branch-chained and has from one to six carbon atoms, as illustrated by carbornethoxy, carbethoxy, carbo-n-propoxy, carbisppropoxy, carbo-n-butoxy, carbo-tert.-butoxy and carbo-n-hexoxy. The compounds of the invention having formulas I, la, lb, Ic, Ie and II are useful both in the free base form and in the form of acid-addition salts, and both forms are within the purview of the invention. The acid-addition salts 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 pqmbined with the free base, pharmaceutically-acceptable salts, that is, salts whose anions are relatively innocuous to the animal organism in pharmaceutical doses of the salts, so that the beneficial cardiotonic properties inherent in 196844 10 -8- 114 I the free base of the cardiotonically-active compounds of the invention are not vitiated by side effects ascribable to the anions. In practicing the invention, it is convenient to use the free base form; however, appropriate pharmaceutically-acceptable salts within the scope of the invention are those derived from mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and an organic acid such as acetic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexyl-sulfamic acid, quinic acid, and the like, giving the hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively. ., The acid-addition salts of said basic compound are i 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. Although pharmaceutically-acceptable salts of said basic compound are preferred, all acid-addition salts are within the scope of our invention. All acid-addition salts are useful as sources of the free base form even if the \ - — 'particular salt per se is desired only as an intermediate product as for example when the salt is formed only for . ... b ^purposes of purification or identification, or when it is -u.sed as an intermediate in preparing a pharmaceutically-\ acceptable salt by ion exchange procedures. 20 -A =- v\ 196844 10 15 20 25 Ui o u. u. O <- til I-< a. N K> OO £ —} o» a UI > UJ o LU cc -9- The molecular structures of the compounds of the invention were assigned on the basis of evidence provided by infrared, nuclear magnetic resonance and mass spectra, and by the correspondence of calculated and found values for the elemental analyses. The manner of making and using the instant invention will now be generally described so as to enable a person skilled in the art of pharmaceutical chemistry to make and use the same, as follows. ffie reaction of an acetylpyridine of the formula PY-00CH3. (IV)"with a di-(lower-alkyl). oxomalonate to produce a di- (lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioate (II), where PY is defined as in formula I above, is carried out by heating,, the reactants at about 80°C. to 120°C. , preferably about 90°C. to 110°C. The reaction is conveniently run on a steam bath. The reaction is preferably run using diethyl or dimethyl oxomalonate. This preparation is illustrated hereinbelow in Examples A-l through A-9. The preparation of lower-alkyl 2,3-dihydro-2-R-3- oxo-6-PY-4-pyridazinecarboxylates by reacting a idi-(lower- \ alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioate (II) with a hydrazine salt of the formula RNHNH *nH An (III), where PY and R are defined as in formula I above and n, x and An are defined as in formula III above, is carried out by heating the reactants at about 60°C. to 100°C., preferably about 75°C. to 85°C., and preferably in the presence of a suitable solvent, e.g., a lower-alkanol having from one to six carbon atoms such as methanol, ethanol or isopropyl alcohol. Other suitable solvents would be dioxane, tetrahydrofuran, pyridine, ethylene glycol, and the like. Preferred R-hydrazine salts are the dihydrochlorides :to A 1968 44 -10- or sulfates. This preparation is illustrated below in i Examples C-2 through C-17. Also note Example B-l where diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate was refluxed with hydrazine monohydrochloride in methanol for a relatively short period (less than 2 hours) to produce ethyl 2,3,4,5-tetrahydro-4-hydroxy-3-oxo-6-(4-pyridinyl)-4-pyri-dazinecarboxylate which, as shown in Example C-l, was readily dehydrated by treating a solution of it in a suitable solvent, e.g., acetonitrile, ethanol, tetrahydrofuran 10 or dioxane with hydrogen chloride to produce ethyl 2,3- dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate. The conversion of the lower-alkyl 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate (la) to the corresponding 4-pyridazinecarboxamide (Ic) was conveniently 15 carried out by bubbling ammonia into a solution of la in an inert appropriate solvent, e.g. , a lov/er—alkanol as hereuibefore defined, preferably ethanol or methanol. Other suitable solvents include i isopropyl alcohol, acetonitrile, tetrahydrofuran, dioxane and the like. The reaction is readily run at room tem-20 perature. This preparation is illustrated below in Examples D-l through D-16. The conversion of a lower-alkyl 2,3-dihydro—2—R—3- oxo-6-PY-pyridazinecarboxylate (la) to the corresponding 2,3-dihydro-2-R-3-oxo-6-PY-pyridazinecarboxylic acid 25 hydrazide (lb) by reaction with hydrazine hydrate or anhydrous hydrazine is carried out by heating the reactants at about 60°C. to about 100°C., preferably about 75°C. to 85°C in a suitable solvent, e.g., a lower-alkanol as hereinbefore defined, ^preferably irethanol, ethanol or isopropyl alcohol. Other 30 ■3 ^-^r^flitable solvents include pyridine, tetrahydrofuran, dioxane A* '» 4' .^ancT"the like. This preparation is illustrated below in ""'Examples E-l through E-16. 1968 -ii- The hydrolysis of a lower-alkyl 2,3-dihydro-2-R-3-oxo-6-PY-pyridazinecarboxylate (la) to the corresponding carboxylic acid (Id) is carried out by heating the ester (la) with-aqueous alkali metal hydroxide solution, e.g., 5 preferably aqueous sodium hydroxide solution, conveniently done by heating the reactants on a steam bath, Alternatively, the hydrolysis of said 4-pyridazinecarboxylate (la) to 4-pyridazinecarboxylic acid (Id) can be carried out by heating the ester (la) with an aqueous solution of 10 a strong inorganic acid, e.g., hydrochloric acid, sulfuric acid, and the like. This hydrolysis is illustrated below in Examples F-l through F-16. The conversion of a 2, 3-dihydro-3-oxo-6—PY-4-pyri-dazinecarboxylic acid hydrazide (lb) to a 4-amino-2-R-6-PY-15 3(2H)-pyridazinone (Ie) is carried out by reacting lb with a reagent capable of converting carboxylic acid hydrazide to amino. This reaction is run by first reacting lb with nitrous acid in aqueous medium at a low temperature, preferably below 5°C., to form the corresponding -4-pyrida-20 zinecarboxylic acid azide in situ and then heating the reaction mixture, preferably about 45 to 65°C., until evolution of nitrogen ceases. This conversion is illustrated below in Example G-l and G-23 thru G-41, The conversion of a 2 , 3-dihydro-2-R-3-oxo—6—PY-4 — 25 pyridazinecarboxamide (Ic) to a 4-airino-2-R-6-PY-3(2H)- pyridazinone (Ie) is carried out by reacting Ic with a jreagent capable of converting carbamyl to amino. The - —-taction is conveniently run by heating an aqueous mixture 1968 4 4 -12- containing the relevant ccitpomd of formula Ic and an alkali metal hypohalite, preferably hypobromite or hypochlorite, and then acidifying the reaction mixture, preferably with an aqueous mineral acid, e.g., hydrochloric acid. The reaction can be run from 5 about 50°C. to 120°C., preferably about 703C, to 100°C. This conversion is illustrated below in Examples G-42 thru G-61. The conversion of a 2-R-6-PY-3- ( 2H) -pyridazinone to a 4-amino-2-R-6-PY-3(2H) -pyridazinone (Ie) by reaction 10 with hydrazine hydrate or anhydrous hydrazine is carried out by heating the reactants in the absence or presence of a suitable inert solvent at about 80CC. to about 130°C., preferably about 90°C. to 110°C. Although the reaction is preferably run using excess hydrazine or hydrazine hydrate 15 as the solvent, it can be run using a suitable inert solvent, e.g., dioxane, ethanol, ethylene glycol dimethyl ether, and the like* Alternatively, the reaction can be run in an autoclave with or without a solvent, This conversion is illustrated below in Examples G-2 through G-22. 20 The preparation of the intermediate 4,5-dihydro- 2-(lower-alkyl)-6-PY-3(2H)-pyridazinones by reacting a 4-oxo-4-PY-butanenitrile with N-R hydrazine salt of a strong inorganic acid or organic sulfonic acid, the resulting 4,5-dihydro-2-(lower-alkyl or lower-hydroxyalkyl)-6-PY-3(2H)- o „ -13- pyridazinones and their use as cardiotonic agents are the subject of our specification '1S6889 filed:22^ April 1S81. The preparation of the intermediate 4,5-dihydro-6-PY-3(2H)-pyridazinones or tautomeric 4,5-dihydro-6-PY-3-5 pyridazinols by reacting .a: '4-oxo-4-PY-butanenitrile is illustrated below in Examples H-l through H-6. The intermediate 4-oxo-4-PY-butanenitriles are generally known compounds, e.g., Stetter et al., Chem. Ber. 107, 210 (1974), and are prepared by generally known methods. 10 The conversion of the intermediate 4,5-dihydro-2- R-6-PY-3(2H)-pyridazinones or where R is H the tautomeric 4,5-dihydro-6-PY-3-pyridazinols by reaction with bromine to the corresponding intermediate 2-R-6-PY-3(2H)-pyridazinones, the latter 2-R-6-PY-3(2H)-pyridazinones and their use as 15 cardiotonics are the subject of-United States patent specification No. 4,304,777. 1 96S 44 -14- The following examples will further illustrate the invention without, however, limiting it thereto. A. Di-(lower-alkyl) Hydroxy[2-oxo-2-(pyridinyl)ethyl]pro-panedioates A-l. Diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate - A mixture containing 8.71 g. of diethyl oxomalonate and 6.06 g. of 4-acetylpyridine was heated on a steam bath for 3 hours and then cooled. A small sample of the reaction mixture in a small test tube was partially solidified by rubbing the sample with a glass rod against the inside of the test tube. The remainder of the cooled reaction mixture was dissolved in 13 ml. of methanol, the solution chilled and seeded with crystals formed in the small test tube and the resulting mixture was allowed to solidify. The solid was collected and washed with small quantity of methanol and air dried to yield 4.7 g. of diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate, m.p. 130-131.5°C. More product was obtained from the mother liquor as follows: the above filtrate was evaporated to dryness on a rotary evaporator while heating on a steam bath and the residue was heated for an additional hour on said bath. Since the residue had not solidified, a small sample in a test tube when covered with ethanol and seeded with the above product gave a solid. The solid was dissolved in a minimum amount warm ethanol, the resulting solution concentrated briefly on a steam bath and then chilled. The resulting solid was collected, washed with a small quantity of ethanol and air-dried to yield another 4.4 g. of diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate, m.p. 127-130°C. The combined two crops (4.7 + 4.4 = 9.1 g. or 61.7% yield) was dissolved in about 23 ml. of hot methanol and the solution then chilled thoroughly. The separated white solid 1 96 3 4-4 -15- was rinsed with a little methanol, air-dried briefly and then dried at 25°C. over P2°5 at Iran* over t*1© weekend, thereby yielding 7.4 g. of diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate, m.p. 131-132°C. Following the procedure described in Example A-l but using in place of 4-acetylpyridine a corresponding molar equivalent quantity of the appropriate 3- or 4-acetylpyridine, it is contemplated that there can be obtained the corresponding diethyl hydroxy[2-oxo-2-(pyridinyl)ethyl]pro-panedioates of Examples A-2 thru A-6. A-2. Diethyl hydroxy[2-oxo-2-(3-pyridinyl)ethyl]propanedioate using 3-acetylpyridine. A-3. Diethyl hydroxy[2-oxo-2-(2-methyl-3-pyridinyl) ethyl] propanedioate using 3-acetyl-2-methylpyridine. A-4. Diethyl hydroxy[2-oxo-2-(5-methyl-3-pyridinyl) ethyl]propanedioate using 3-acetyl-5-methylpyridine. A-5. Diethyl hydroxy[2-oxo-2-(3-ethyl-4-pyri-dinyl)ethyl]propanedioate using 4-acetyl-3-ethylpyridine. A-6. Diethyl hydroxy[2-oxo-2-(2,6-dimethyl-4-pyridinyl)ethyl]propanedioate using 4-acetyl-2,6-dimethyl-pyridine. Following the procedure described in Example A-l but using in place of diethyl oxomalonate a molar equivalent quantity of the appropriate di-(lower-alkyl) oxomalonate, it is contemplated that there can be obtained the corresponding di-(lower-alkyl) esters of Examples A-7 through A-9. A-7. Dimethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate. A-8. Di-n-propyl hydroxy[2-oxo-2-(4-pyridinyl)-ethyl]propanedioate. 1 96 8 4 4 -16- A-9. Diisobutyl hydroxy[2-oxo-2-(4-pyridinyl)-ethyl]propanedioate. B. Lower-alkyl 2,3,4,5-Tetrahydro-2-R-4-hydroxy-3-oxo-6-PY-4-pyridazinecarboxylates B-l. Ethyl 2,3,4,5-Tetrahydro-4-hydroxy-3-oxo-6-(4-pyridiny1)-4-pyridazinecarboxylate - A 5.9 g. portion of diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate was added to a warm solution containing 1.4 g. of hydrazine monohydrochloride in 150 ml. of methanol, the resulting reaction mixture was refluxed gently for 1 hour and 45 minutes, cooled briefly and then stripped to dryness on a roto vaporizer. The resulting gummy residue was warmed with a small quantity of acetonitrile to produce a crystalline material; the mixture was then chilled. The crystals were collected, washed with a small quantity of acetonitrile and air-dried to yield 2.25 g. ethyl 2,3,4,5-tetrahydro-4-hydroxy-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate -hydrochloride, m.p. 160-163°C. with decomposition. A 1.65 g. portion of this monohydrochloride was dissolved in about 10 ml. of water, the solution filtered and solid sodium bicarbonate was added in small portions until the evolution of carbon dioxide ceased. The precipitated white solid was collected, rinsed with water and dried over P2°5 at 11011 • and 25°C. for six hours to yield 1.2 g. of ethyl 2,3,4,5-tetrahydro-4-hydroxy-3-oxo-6-(4-pyridinyl)-4-pyridazine-carboxylate, m.p. 193-195°C. with decomposition. As shown in Example C-l, the 4-hydroxy-tetrahydro product of the immediately preceding paragraph is readily dehydrated by treating it with a strong inorganic acid or an organic sulfonic acid, preferably hydrogen chloride, to produce ethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-Pvri- 19 684 4 -17- dazinecarboxylate. Thus, it appears that the conversions shown in Examples C-2 through C-17 go through the corresponding lower-alkyl 2,3,4,5-tetrahydro-4-hydroxv-3-oxo-6-PY-4-pyrida2inecarboxylates, none of which was actually isolated other than the product of Example B-l. C. Lower-alkyl 2,3-Dihydro-2-R-3-oxo-6-PY-4-pyridazine-carboxylates C-l. Ethyl 2,3-Dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate - This preparation shows the con-10 version of Example B-l to the entitled compound. Into a one liter portion of acetonitrile was bubbled gaseous hydrogen chloride with stirring for about 5 minutes. To this mixture was added 9.5 g. of ethyl 2,3,4,5-tetrahydro-4-hydroxyi-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate and hydrogen 15 chloride was bubbled into the mixture for an additional 15 minutes. The reaction mixture was stirred for 1 hour whereupon the solid separated. The reactiqn mixture was stirred for an additional 2 hours and then allowed to stand at room temperature overnight (about 15 hours). The white 20 solid was collected, dried in a vacuum oven for 2 hours at 40°C. over P2°5 to y^-el^ 8.0 g. of ethyl 2,3-dihydro-3-oxo-6- (4-pyridinyl)-4-pyridazinecarboxylate dihydrochloride, m.p. 212-220°C. with decomposition. The hydrochloride salt was dissolved in a minimum quantity of water and solution 25 basified with solid sodium bicarbonate. The resulting \ precipitate was collected, washed with water and dried in a vacuum oven over P2°5 at 25°C. overnight to yield 5.5 g. of "/j1ethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecar-boxy late, m.p. 196-197°C. ■;.3/EP 1 96 8 4 4 -18- C-2. Ethyl 2f 3-Dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate - The following synthesis of the entitled compound was carried out directly using Example A-1. To a warm solution containing 16.0 g. of hydrazine dihydrochloride in 1 1. of absolute ethanol was added with stirring 44.25 g. of diethyl hydroxy[2-oxo-2-(4-pyridinyl)-ethyl]propanedioate rinsed in with 250 ml. of absolute ethanol and the resulting reaction mixture was refluxed for 19 hours. About 300 ml. of the ethanol was distilled off under reduced pressure and the remaining reaction mixture was evaporated on a roto vaporizer to obtain a tan solid. The solid was slurried with 100 ml. of water and the mixture transferred to a 500 ml. flask, rinsing the material with an additional 25 ml. of..water. To the aqueous mixture was cautiously added solid sodium bicarbonate until evolution of carbon dioxide ceased. The solid was collected, rinsed with water, air-dried and then dried in a vacuum oven over P2®5 at 10 mm. in 25°C. to yield ethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate. C-3. Ethyl 2,3-Dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate - A mixture containing 26 g. of 1-methylhydrazine dihydrochloride, 148 g. of diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate in 1500 ml. of absolute ethanol was refluxed with stirring overnight (about 15 hours), the reaction mixture was heated in vacuo to remove the solvent and the residual gummy material was taken up in about 600 ml. of water and the aqueous solution basified with solid potassium carbonate until basic to litmus. The precipitated solid was collected and later combined with additional product obtained from the filtrate which had been found to still be acidic. The filtrate was -19- basified with 10% aqueous potassium carbonate and the alkaline mixture was extracted with chloroform and the chloroform extract heated in vacuo to remove the solvent. The resulting solid product was combined with the above-said product and the combined material was recrystallized from ethyl acetate and n-hexane and dried first at 40°C. for 17 hours and then at 60°C. for 17 hours to produce 34 g. of ethyl 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate, m.p- 128-129°C. Acid-addition salts of ethyl 2,3-dihydro-2-methyl-3-0x0-6-(4-pyridinyl)-4-pyridazinecarboxylate are conveniently prepared by adding to a mixture of 1 g. of ethyl 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate in about 20 ml. of aqueous methanol the appropriate acid, e.g., ,, hydrochloric acid, methanesulfonic acid or sulfuric acid, to a pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, -e.g., hydrochloride, methanesulf onate or sulfate, respectively. Alternatively, the lactate or hydrochloride acid-addition salt of ethyl 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of ethyl 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate and lactic acid or hydrochloric acid, respectively. Following the procedure described above in Example C-2 but using in place of diethyl hydroxy[2-oxo-2-(4-pyri-vr - dinyl)ethyl]propanedioate a molar equivalent quantity of the \ ^pR\$^ppropriate diethyl hydroxy[2-oxo-2- (pyridinyl)ethyl]pro--r panedioate, it is contemplated that there can be obtained 1^96 3 4 4 -20- the corresponding ethyl 2,3-dihydro-3-oxo-6-(pyridinyl)-4-pyridazinecarboxylates of Examples C-4 thru C-8. C-4. Ethyl 2,3-dihydro-3-oxo-6-(3-pyridinyl)-4-pyridazinecarboxylate. C-5. Ethyl 2,3-dihydro-6-(2-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylate. C-6. Ethyl 2,3-dihydro-6-(5-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylate. C-7. Ethyl 6-(3-ethyl-4-pyridinyl)-2,3-dihydro-3-oxo-4-pyridazinecarboxylate. C-8. Ethyl 2,3-dihydro-6-(2,6-dimethyl-4-pyri-dinyl)-3-oxo-4-pyridazinecarboxylate. Following the procedure described in Example C-3 but using in place of 1-methylhydrazine dihydrochloride a molar equivalent quantity of the corresponding 1-R-hydrazine dihydrochloride or other salt of a strong inorganic acid or an organic sulfonic acid, it is contemplated that there can be obtained the corresponding ethyl 2,3-dihydro-2-R-3-oxo-6- (4-pyridinyl)-4-pyridazinecarboxylates of Examples C-9 thru C-17. C-9. Ethyl 2-ethy1-2,3-dihydro-3-oxo-6-(4-pyridinyl) -4-pyridazinecarboxylate. C-10. Ethyl 2-isopropyl-2,3-dihydro-3-oxo-6-(4-pyridiny1)-4-pyridazinecarboxylate. C—11. Ethyl 2,3-dihydro-3-oxo-2-n-propy1-6- (4-pyridinyl)-4-pyridazinecarboxylate. C-12. Ethyl 2,3-dihydro-2-isobutyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate. C-13. Ethyl 2-n-hexyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate. 196844 -21- C-14. Ethyl 2,3-dihydro-2-(2-hydroxyethyl)-3-oxo 6- (4-pyridinyl)-4-pyridazinecarboxylate. C-15. Ethyl 2,3-dihydro-2-(2-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate. C-16. Ethyl 2,3-dihydro-2-(3-hydroxvpropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate. C-17. Ethyl 2,3-dihydro-2-(4-hydroxybutyl)-3-oxo 6- (4-pyridinyl)-4-pyridazinecarboxylate. D. Lower-alkyl 2,3-Dihydro-2-R-3-oxo-6-PY-4-pyridazine-carboxamides D-l. 2,3-Dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide - Ammonia was bubbled into 800 ml. of absolute ethanol with stirring over a period of 20 minutes. To the mixture was then added 50 g. of ethyl 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate; the reaction mixture was stirred for 40 minutes and then allowed to stand at room temperature overnight. The precipitate was collected, washed with absolute ethanol recrystallized from absolute ethanol and dried in a vacuum oven overnight to yield 15 g. of 2,3-dihydro-2-methyl-3-oxo 6-(4-pyridinyl)-4-pyridazinecarboxamide, m.p. 234-235°C. Another 17.5 g. of product was obtained by distilling off the solvent from the mother liquor. Acid-addition salts of 2,3-dihydro-2-methyl-3-oxo 6-(4-pyridinyl)-4-pyridazinecarboxamide are conveniently prepared by adding to a mixture of 1 g. of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide in .^^^out 20 ml. of aqueous methanol the appropriate acid, e.g. hydrochloric acid, methanesulf onic acid or sulfuric acid, to a pfLw>f about 2 to 3, chilling the mixture after partial -^^jtaporation and collecting the precipitated salt, e.g., 196844 -22- hydrochloride, methanesulf onate or sulfate, respectively. Alternatively, the lactate or hydrochloride acid-addition salt of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyri-dinyl)-4-pyridazinecarboxamide and lactic acid or hydrochloric acid, respectively. Following the procedure described in Example D-l 10 but using in place of ethyl 2,3-dihydro-2-methyl-3-oxo-6-(4- pyridinyl)4-pyridazinecarboxylate a molar equivalent quantity of the appropriate ethyl 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate, it is contemplated that there can be obtained the corresponding 2,3-dihydro-2-R-3-oxo-6-PY-4-15 pyridazinecarboxamides of Examples D-2 thru D-16. D-2. 2,3-Dihydro-3-oxo-6-(4-pyridinyl)-4-pyri-dazinecarboxamide. D-3. 2,3-Dihydro-3-oxo-6- (3-pyridinyl)-4-pyri-dazinecarboxamide. 20 D-4. 2,3-Dihydro-6-(2-methyl-3-pyridinyl)-3-oxo- 4-pyridazinecarboxamide. D-5. 2,3-Dihydro-6-(5-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxamide. D-6. 6-(3-Ethyl-4-pyridinyl)-2,3-dihydro-3-oxo-4-^5 pyridazinecarboxamide. D-7. 2,3-Dihydro-6-(2,6-dimethyl-4-pyridinyl)-3-oxo-4-pyridazinecarboxamide. D-8. 2-Ethyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-®§yrida zinecarboxamide. D-9. 2-Isopropyl-2, 3-dihydro-3-Qxo-6-(4-pyri- V •- dinyl)-4-pyridazinecarboxamide. 1 96 3 4 D-10. 2,3-Dihydro-3-oxo-2-n-propyl-6-(4-pyri-dinyl)-4-pyridazinecarboxamide. D-ll. 2,3-Dihydro-2-isobutyl-3-oxo-6-(4-pyridinyl) -4-pyridazinecarboxamide. D-12. 2-n-Hexyl-2,3-dihydro-3-oxo-6-(4-pyridinyl) -4-pyridazinecarboxamide. D-13. 2,3-Dihydro-2-(2-hydroxyethyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide. D-14. 2,3-Dihydro-2-(2-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide. D-15. 2,3-Dihydro-2-(3-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide. D-16. 2,3-Dihydro-2-(4-hydroxybutyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide. E. 2,3-Dihydro-2-R-3-oxo-6-PY—4-pyridazinecarboxylic Acid Hydrazides E-l. 2,3-Dihydro-3-oxo-6-(4-pyridinyl)-4-pyri-dazinecarboxylic Acid Hydrazide - A mixture containing 10 g. of ethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecar-boxylate and 300 ml. of absolute ethanol was heated on a steam bath with stirring for about 10 minutes. To the resulting stirred solution was"added 4 g. of anhydrous hydrazine whereupon a solid began precipitating out within 5 minutes. The reaction mixture was heated for about 1 hour with stirring. The separated solid was collected, dried in a vacuum oven at 65°C. over P2°5 overni-9ht to yield 9.4 g. of 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide, m.p. > 300°C. 196344 -24- E-2- 2,3-Dihydro-2-inethyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic Acid Hydrazide - This preparation was carried out following the procedure described in Example E-1 using 8.5 g. of ethyl 2,3-dihydro-2-methyl-3-oxo-6(4-pyridinyl)-4-pyridazinecarboxylate, 10.8 g. of anhydrous hydrazine and 150 ml. of ethanol. The reaction was run a second time using the same quantities of reactants. The products were combined and recrystallized from absolute ethanol to produce 10 g. of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide, m.p. 209-210°C. A second crop of 3 g., m.p. 212-213°C. was obtained from the mother liquor. > Acid-addition salts of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide are conveniently prepared by adding to a mixture of 1 g. of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide in about 20 ml. of- aqueous methanol the appropriate acid, e.g., hydrochloric acid, methanesulfonic acid or sulfuric acid, to a pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., hydrochloride, methanesulfonat? or sulfate, respectively. Alternatively, the lactate or hydrochloride acid-addition salt of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide and lactic acid or hydrochloric acid, respectively. OS 1 &< q a • v W O ^ -25- Following the procedure described in Example E-l but using in place of ethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl) -4-pyridazinecarboxylate a molar equivalent quantity of the appropriate ethyl 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate, it is contemplated that there can be obtained the corresponding 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazides of Examples E-3 thru E-16. E-3. 2,3-Dihydro-3-oxo-6-(3-pyridinyl)-4-pyridazinecarboxylic acid hydrazide. E-4. 2,3-Dihydro-6-(2-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylic acid hydrazide. E-5. 2,3-Dihydro-6-(5-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylic acid hydrazide. E-6. 6-(3-Ethyl-4-pyridinyl)-2,3-dihydro-3-oxo-4-pyridazinecarboxylic acid hydrazide. E-7. 2,3-Dihydro-6-(2,6-dimethyl-4-pyridinyl)-3-oxo-4-pyridazinecarboxylic acid hydrazide. E-8. 2-Ethyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide. E-9. 2-Isopropyl-2,3-dihydro-3-oxo-6-(4-pyridinyl) -4-pyridazinecarboxylic acid hydrazide. E-10. 2,3-Dihydro-3-oxo-2-n-propyl-6-(4-pyridinyl) -4-pyridazinecarboxylic acid hydrazide. E-ll. 2,3-Dihydro-2-isobutyl-3-oxo-6-(4-pyridinyl) -4-pyridazinecarboxylic acid hydrazide. E-12. 2-n-Hexyl-2,3-dihydro-3-oxo-6-(4-pyri-dinyl)-4-pyridazinecarboxylic acid hydrazide. E-13. 2,3-Dihydro-2-(2-hydroxyethyl)-3-oxo-6- (4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide. E-14. 2,3-Dihydro-2-(2-hydroxypropyl)-3-oxo-6-(4- 1-96844 -26- E-15. 2 , 3-Dihydro-2- (3-hydroxypropyl) r3-oxo-6- (4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide. E-16. 2,3-Dihydro-2-(4-hydroxybutyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide. F. 2,3-Dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic Acids F-l. 2,3-Dihydro-3-oxo-6- (4-pyridinyl)-4-pyridazinecarboxylic Acid - A mixture containing 10 g. of ethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate and 100 ml. of 5% aqueous sodium hydroxide solution was 10 heated on a steam bath for 6 hours, allowed to cool to room temperature and then treated slowly with acetic acid until solid began to separate. The mixture was allowed to stand until no more solid separated and the solid was then collected, dried in a vacuum oven over p2°5 at 45°C. to yield 7.7 g. of 15 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid, m.p. ^ 310°C. i F-2 ^ 2,3-Dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic Acid - To a mixture containing 29.4 g of diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate and 20 40 ml. of absolute ethanol was added 4.6 g. of 1-methylhydra- zine which had previously been treated with 6 ml. of 6N hydrochloric acid. The reaction mixture was refluxed overnight and then the solvent distilled off in vacuo. The remaining yellow residue was treated with 300 ml. of 20% ^_25 aqueous sodium hydroxide solution and the mixture heated on w a steam bath overnight. The reaction mixture was allowed to cool to room temperature and the separated solid was collected. The solid was recrystallized from 120 ml. of acetic acid using decolorizing charcoal and the hot filtrate after - -removal of the decolorizing charcoal was treated with 120 ml. of hot water. The resulting solution was allowed to 'Jt>J 2 1 _ 1 96 8 4 4 -27- cool and the resulting mixture containing crystalline product was allowed to stand over the weekend. The solid was collected and dried in a vacuum oven at 80°C. over P-O.. z D overnight to yield 9.4 g. of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid, m.p. 267-268°C. Following the procedure described in Example F-l but using in place of ethyl 2,3-dihydro-3-oxo-6- (4-pyridinyl) -4-pyridazinecarboxylate a molar equivalent quantity of the appropriate ethyl 2,3-dihydro-2-R-3-oxo-6-PY-4-10 pyridazine carboxylate, it is contemplated that there can be obtained the corresponding 2,3-dihydro-2-R-2,3-dihydro-3-^ oxo-6-PY-4-pyridazinecarboxylic acids of Example F-3 thru F- 16. F-3. 2,3-Dihydro-3-oxo-6-(3-pyridinyl)-4-pyri-15 dazinecarboxylic acid. F-4. 2,3-Dihydro-6-(2-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylic acid. F-5. 2,3-Dihydro-6-(5-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylic acid. 20 F-6. 6-(3-Ethyl-4-pyridinyl)-2,3-dihydro-3-oxo-4- pyridazinecarboxylic acid. , F-7. 2,3-Dihydro-6-(2,6-dimethyl-4-pyridinyl)-3-oxo-4-pyridazinecarboxylic acid. F-8. 2-Ethy1-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-25 pyridazinecarboxylic acid. m F-9. 2-Isopropyl-2,3-dihydro-3-oxo-6-(4-pyridinyl) -4-pyridazinecarboxylic acid. F-10. 2,3-Dihydro-3-oxo-2-n-propyl-6-(4-pyridinyl) -4-pyridazinecarboxylic acid. 30 F-ll. 2,3-Dihydro-2-isobutyl-3-oxo-6-(4-pyri dinyl) -4-pyridazinecarboxylic acid. * o tr Z -28- F-12. 2-n-Hexy1-2,3-dihydro-3-oxo-6-(4-pyridinyl) -4-pyridazinecarboxylic acid. F-13. 2,3-Dihydro-2-(2-hydroxyethyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid. F-14. 2,3-Dihydro-2-(2-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid. F-15. 2,3-Dihydro-2-(3-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid. F-16. 2,3-Dihydro-2- (4-hydroxybutyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid. G. 4-Amino-6-PY-2-R-3(2H)-pyridazinones G-l. 4-Amino-6-(4-pyridinyl)-3(2H)-pyridazinone -The following procedure describes the preparation of the entitled compound from the corresponding 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide (Example E-l). To a mixture containing 28 g. of 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide and 700 ml. of concentrated hydrochloric acid and 400 ml. of water, said mixture cooled in an ice-sodium chloride bath was added a solution containing 20 g. of sodium nitrite in 75 ml. of water with vigorous stirring over a 30 minute period keeping the internal temperature below 5°C. The cold reaction mixture was stirred in the ice-salt bath for an additional 45 minutes and then at room temperature for 30 minutes and then heated gently on a steam bath. When the internal temperature reached 55-60°C. evolution of nitrogen became rapid. The source of steam was removed until the 1 9S S 4 4 -29- reaction moderated. The reaction mixture was then heated on a steam bath for 2 hours and chilled in an ice bath. The separated solid was filtered off and washed with water. (See below for identification of this solid.) The combined aqueous acidic filtrate and washings were concentrated to dryness in vacuo and to the residue was added aqueous ammonium hydroxide solution until the mixture was slightly basic. The mixture was reacidified with acetic acid and cooled in an ice bath. The resulting yellow solid was collected, washed with water and dried. This solid (14.2 g.) was suspended in 50 ml. of 10% potassium bicarbonate solution, treated with 100 ml. of water and the resulting mixture stirred for 1 hour at room temperature. The yellow solid was collected, washed with water and dried in an oven at 90°C. The solid was dissolved in 300 ml. of 6N hydrochloric acid by heating on a steam bath. The hot solution was filtered and the filtrate was allowed to stand at room temperature overnight. The bright yellow crystalline product was collected, washed with a small amount of distilled water and dried in an oven at 85°C. to yield 6.8 g. of 4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone monohydrochloride monohydrate, m.p. > 340°C. The above tan solid, which had been filtered off from the acetic reaction mixture and washed with water, was dissolved in aqueous ammonium hydroxide solution and the solution filtered. The filtrate was acidified with acetic acid whereupon solid crystallized. The mixture was cooled in an ice bath. The crystalline material was collected, washed with water and dried in an oven at 80°C. to yield 13.5 g. of material, m.p. >320°C., which was identified by its NMR spectrum to be the same as Example F-l, that is, 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4- 1 « 4 -30- pyridazinecarboxylic acid. The above procedure of Example G-l first procedes through the acid azide as seen by the following isolation of the acid azide as its monohydrochloride: To a solution chilled in an ice bath and containing 3.0 g. of 2,3-dihydro-3-0x0-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide and 60 ml. of 6N hydrochloric acid was added dropwise with stirring a solution containing 3.0 g. of sodium nitrite in 10 ml. of water over a 30 minute period. The reaction mixture was then stirred for an additional 1 hour, allowing the reaction mixture to warm up to room temperature. The separated solid was collected, washed with water and dried in a vacuum oven over p2°5 at 25°C. for 48 hours to yield 3.0 g. of 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid azide monohydrochloride, m.p. ) 300°C. G--2. 4-Amino-6- (4-pyridinyl) -3 (2H) -pyridazinone -The following procedure describes the preparation of the entitled compound by reacting hydrazine with 6-(4-pyri-dinyl)-3(2H)-pyridazinone, the tautomeric form of 6-(4-pyridinyl)-3-pyridazinol. A mixture containing 10 g. of 6-(4-pyridinyl)-3(2H)-pyridazinone and 70 ml. of hydrazine hydrate was heated on a steam bath for 3 days and the excess hydrazine distilled off in vacuo. The remaining residue was heated with about 300 ml. of methanol and the solid was collected by filtration. The solid was combined with the corresponding solid obtained from another run starting with 15.7 g. of 6-(4-pyridinyl)-3(2H)-pyridazinone and 21 ml. of hydrazine hydrate and the combined solids were dissolved in aqueous potassium carbonate solution and reprecipitated by addition of acetic acid. The precipitate was dried for 9 hours at 40°C. over P2°5 and then overnight at 80°C. After 10 1-96844 -31- its NMR spectrum had shpwn thp solid still to contain acetic acid, it was next dried in a vacuum oven at 80°C. for 2 days to yield 18.2 g. (69% yield) of 4-amino-6-(4-pyridinyl)-3 (2H)-pyridazinone, m.p. ) 300°C. Acid-addition salts of 4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone are conveniently prepared by adding to a mixture of 1 g. of 4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone in about 20 ml. of aqueous methanol the appropriate acid, e.g., hydrochloric acid, methanesulfonic acid or sulfuric acid, to a pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., hydrochloride, methane sulfonate., or sulfate, respectively. Also, the lactate or hydrochloride acid-addition salt of 4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of 4-amino-6- J (4-pyridinyl)-3(2H)-pyridazinone and lactic acid,or hydrochloric acid, respectively. G-3. 4-Amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone, m.p. 229-235°C., 6.4 g. , was prepared following the procedure described in Example G-2 using 12 g. of 2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone and 100 ml. of hydrazine hydrate, followed by recrystallization from acetonitrile using decolorizing charcoal. Acid-addition salts of 4-amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone are conveniently prepared by adding to a mixture of 1 g. of 4-amino-2-methyl-6-(4-pyri-rT^^^ dinyl)-3 (2H) -pyridazinone in about 20 ml. of aqueous methanol ^ ^ r.r*~5f-jcfehe appropriate acid, e.g., hydrochloric acid, methane- it. l' ""^"sulfonic acid or sulfuric acid, to a pH of about 2 to 3, i -chilling the mixture after partial evaporation and collecting 20 6844 10 15 20 25 -32- the .precipitated salt, e.g., hydrochloride, m^thanesulfonate or sulfate, respectively. Also, the lactate or hydrochloride acid-addition salt of 4-amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of 4-amino-2-methy1-6-(4-pyridinyl)-3(2H)-pyridazinone and lactic acid or hydrochloric acid, respectively . Following the procedure described in Example G-2 but using in place of 6-(4-pyridinyl)-3(2H)-pyridazinone a molar equivalent quantity of the appropriate 2-R-6-PY-3(2H)-pyridazinone, it is contemplated that there can be obtained the 4-amino-2-R-6-PY-3(2H)-pyridazinones of Examples G-4 thru G-22. 4-Amino-6-(3-pyridinyl)-3(2H)-pyridazinone. 4-Amino-6-(2-methyl-3-pyridinyl)-3(2H)- 4-Amino-6-(3-ethyl-4-pyridinyl)-3(2H)- '^lEPATBSTO^a - j 2tAPR193?yridazi G-4. G-5. pyridazinone. G-6. 4-Amino-6-(5-methyl-3-pyridinyl)-3(2H)-pyridazinone. G-7. pyridazinone. G-8. 4-Amino-6-(2,6-dimethyl-4-pyridinyl)-3(2H)-pyridazinone. G-9. 4-Amino-2-ethyl-6- (4-pyridinyl)-3 (2H)-pyridazinone. G-10. 4-Amino-2-isopropyl-6-(4-pyridinyl)-3(2H)-pyridazinone. G-ll. iSSWir-. 4-Amino-2-n-propyl-6-(4-pyridinyl)-3(2H)-inone. G-12. 4-Amino-2-isobutyl-6-(4-pyridinyl)-3(2H)- -33- G-13. 4-Amino-2-n-hexyl-6-(4-pyridinyl)-3(2H)-pyridazinone. G-14. 4-Amino-2-(2-hydroxyethyl)-6-(4-pyridinyl)-3(2H)-pyridazinone. G-15. 4-Amino-2-(2-hydroxypropyl)-6-(4-pyridinyl) -3 (2H)-pyridazinone. G-16. 4-Amino-2-(3-hydroxypropyl)-6-(4-pyridinyl) -3(2H)-pyridazinone. G-17. 4-Amino-2-(4-hydroxybutyl)-6-(4-pyridinyl)-3(2H)-pyridazinone. G-18. 4-Amino-2-methy1-6-(3-pyridinyl)-3(2H)-pyridazinone. G-19. 4-Amino-2-methy1-6-(2-methyl-3-pyridinyl)-3 (2H)-pyridazinone. G-20. 4-Amino-2-methy1-6-(5-methyl-3-pyridinyl)-3(2H)-pyridazinone. G-21. 4-Amino-6-(3-ethyl-4-pyridinyl)-2-methy1-3(2H)-pyridazinone. G-22. 4-Amino-2-methy1-6-(2,6-dimethyl-4-pyri-dinyl)-3(2H)-pyridazinone. Following the procedure described in Example G-l but using in place of 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide a corresponding molar equivalent quantity of the appropriate 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide, it is contemplated that there can be obtained as Examples G-2 3 thru G-41 the corresponding 4-amino-6-PY-2-R-3(2H)-pyridazinones obtained in Examples G-4 thru G-22, respectively. G-42. 4-Amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone - To a solution containing 9.0 g. of sodium hydroxide in 130 ml. of water kept at 0°C. is added dropwise 1 96 8 4 4 -34- with stirring 2.3 ml. of bromine. To the aqueous mixture is added with stirring 8.0 g. of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazincarboxamide and the resulting reaction mixture is heated on a steam bath for four hours. The reaction mixture is cooled to room temperature, acidified slowly with 6N hydrochloric acid and the resulting acidic mixture is stirred for an additional twenty-five minutes. The acidic mixture is neutralized with 10% aqueous potassium bicarbonate solution and the mixture cooled. The precipitate is collected, washed, dried, recrystallized from acetonitrile, collected, washed with water and dried about 15 hours in a vacuum oven at 65°C. over P2°5 to 4- amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone. Following the procedure described in Example G-42 but using in place of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide a molar equivalent quantity of the appropriate 2,3-dihydro-3-oxo-6-PY-2-R-4-pyridazinecarboxamide, it is contemplated that there can be obtained as Examples G-43 thru G-61 the corresponding 4-amino-6-PY-2-R-3(2H)-pyridazinones obtained in Examples G-4 thru G-22,. respectively. H, 4, 5^Dihydro'-2~R-6-PY--3 (.2H) -pyridazinones 196844 -35- H-l 4,5-Dihydror6-(4-pyridinyl) -3(2H)-pyri dazinone - A mixture containing 2.4 g. of 4-oxo-4-(4-pyridinyl) butanenitrile (same as V-oxo-T-(4-pyridinyl)butyro-nitrile), 1.96 g. of hydrazine sulfate, 100 ml. of absolute ethanol and 100 ml. of water was refluxed with stirring overnight (about 15 hours). The reaction mixture was heated in vacuo to remove the solvent mixture. The remaining residue was taken up in water and filtered. The filtrate was neutralized with 10% aqueous sodium bicarbonate solution and a yellow solid separated. The solid was collected, washed with water, dried in vacuo over p205 ^or ^our hours. Its nuclear magnetic resonance (nmr) and mass spectra were found to be consistent with that of the desired product but showed traces of impurities. The solid was then recrystallized from absolute ethanol, dried in vacuo over ^2^5 overnight to yield, as golden crystals, 0.9 g. of 4,5- l dihydro-6-(4-.pyridinyl)-3(2H)-pyridazinone, m.p. 185-187°C. which is tautomeric with 4,5-dihydro-6-(4-pyridinyl)- 3-pyridazinol. The above reaction also can be run by using a molar equivalent quantity of hydrazine dihydrochloride or hydrazine di(methanesulfonate) in place of hydrazine sulfate. Acid-addition salts of 4,5-dihydro-6-(4-pyri-dinyl)-(2H)-pyridazinone are conveniently prepared by adding' to a mixture of 1 g. of 4,5-dihydro-6-(4-pyridinyl)-3 (2H) -pyridazinone in about 20 ml. of aqueous methanol the appropriate acid, e.g., hydrochloric acid, methanesulfonic acid or sulfuric acid, to a pH of about 2 to 3, chilling the - ^-inixture after partial evaporation and collecting the pre-' C¥2Dcipitated salts, e.g., hydrochloride, methanesulfonate, or sulfate, respectively. Also, the lactate or hydrochloride -36- acid-addition salt is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of 4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone and lactic acid or hydrochloric acid, respectively. 5 Following the procedure described in Example H-l but using in place of 4-oxo-4-(4-pyridinyl)butanenitrile a molar equivalent quantity of the corresponding 4-oxo-4-PY-butanenitrile, it is contemplated that there can be obtained the corresponding 4,5-dihydro-6-PY-3(2H)-pyridazinones of 10 Examples h-2 thru H-6. H-2. 4,5-Dihydro-6-(3-pyridinyl)-3-(2H)-pyridazinone . H-3. 4,5-Dihydro-6-(2-methy1-3-pyridinyl)-3(2H)-pyridazinone. 15 H-4. 4,5-Dihydro-6-(5-methyl-3-pyridinyl)-3-(2H)- pyridazinone. H-5. 6-(3-Ethyl-4-pyridinyl)-4,5-dihydro-3(2H)-pyridazinone. H-6., 4, 5-Dihydro-6-(2,6-dimethyl-4-pyridinyl)-20 3(1H)-pyridazinone. 196844 * -37- The usefulness of the compound of Formula I where R1 is amino, carbairyl, airinocarbamyl or lcwer-cartoalKoxy, and R is lower-alkyl or lower-hydroxyalkyl, or salts thereof as cardiotonic agents is demonstrated by their effectiveness 5 in standard pharmacological test procedures, for example, in causing a significant increase in contractile force of the isolated cat atria and papillary muscle. Detailed descriptions of these test procedures appear in U.S. Patent 4,072,746 and New Zealand"Patent' Specification No 182,270. -10 When tested by said isolated cat atria and pap illary muscle procedure, said . 2-r-4-r'-6-PY-3(2H)-; pyridazinones or pharmaceutically-acceptable acid-addition salts thereof at doses of 30, 100 and/or 300 yg./ml., were found to cause significant increases, that is, greater than 15 25% in papillary muscle force and/or significant increases, that is, greater than 25%, in right atrial force, while causing a lower percentage increase in right atrial rate. For example, when tested at said dose levels by this procedure, the following preferred compounds of Formula Ie 20 were found to cause increases of from about 3 0% to over 200% in papillary muscle force and/or right atrial force: the compounds of Examples G-2 and G-3. When tested at said dose levels by this procedure, the following preferred compounds of Formula la, Ic, and lb were found to cause 25 increases of 28 to 72% in papillary muscle force and/or right atrial force: the compounds of Examples C-3, D-l and E-2. N.2. PATENT OF F>C6 29JUL1983 RECEIVED, 196844 When tested by said anesthetized dog procedure, the compounds of Formula Ie or pharmaceutically-acceptable acid-addition salts thereof at doses of 1.0, 3.0 and/or 10 mg./kg. administered intravenously were found to cause 5 significant increases, that is, 25% or greater, in cardiac contractile force or cardiac contractility with lower changes in heart rate and blood pressure. For example, when tested at said dose levels by this procedure, a preferred compound, Example G-2, was found to cause in-10 creases of 46% and greater in contractile force and lower changes in heart rate and blood pressure. In clinical practice a cardiotonically active compound or acid addition salt thereof of the present invention-will normally be administered orally or parenterally in a wide 15 variety of dosage form. Solid composition for oral administration of the cardiotonically active compounds of the invention include compressed tablets, pills, powders and granules. In such solid compositions, at least one of the active compounds 20 is admixed with at least one inert diluent such as starch, calcium carbonate, sucrose or lactose. These compositions can also contain additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate, talc and the like, I 1 96 £ 4 4 -39- Liquid composition for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. 5 Besides inert diluents such compositions can also contain adjuvants, such as wetting and suspending agents, and sweetening, flavoring, perfuming and perserving agents. According to the invention, the compounds for oral admin- </div>

Claims

-40- istration also include capsules of absorbable material, such as gelatin, containing said active component with or without the addition of diluents or excipients. Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions can also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents. They can be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of sterilising agents in the compositions, by irradiation or by heating. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use. The percentages of active component in the said composition and method for increasing cardiac contractility can be varied so that a suitable dosage is obtained. The dosage administered to a particular patient is variable, depending upon the clinician's judgement using as the criteria: the route of administration, the duration of treatment, the size and condition of the patient, the potency of the active component and the patient's response thereto. An effective dosage amount of active component can thus only be determined by the clinician considering all criteria and utilizing the best judgement on the patient's behalf. 1 What we claim is: 1. A 2-R-4-R'-6-PY-3(2H)-pyridazinone having the Formula I (herein) or an acid-addition salt thereof, where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, R is hydrogen, lower-alkyl or lower-hydroxyalkyl, and R* is amino, carbamyl, carboxy, -aminocarbamyl or lower-carbalkoxy. 2. A compound according to claim 1, where PY is 4-pyridinyl or 3-pyridinyl. 3. A compound according to claim 1 or 2, where R' is amino. 4. A compound according to claim 3, where R is hydrogen, methyl, ethyl or 2-hydroxyethyl. 5. 4-Amino-6-(4-pyridinyl)-3(2H)-pyridazinone or a pharmaceutically-acceptable acid-addition salt thereof. 6. 4-Amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone or a pharmaceutically-acceptable acid-addition salt thereof. 7» A compound according to claim 1 or 2, where R' is carbamyl, aminocarbamyl, lower-carbalkoxy or carboxy. 8. A compound according to claim 7, where R is hydrogen, methyl or ethyl. 9. A process for preparing a compound according to claim 3 or 4, which comprises reacting a 2-R-6-PY-3(2H)-pyridazinone with hydrazine and, if desired, converting a free base obtained into an acid-addition salt thereof. 10. A process for preparing a compound according to claim 3 or 4, which comprises reacting a 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxamide with a reagent capable of converting carbamyl to amino and, if desired, converting a free base obtained into an acid-addition salt thereof. 11. A process for preparing a compound according to claim 3 or 4, which comprises reacting a 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide with a reagent capable of converting carboxylic acid hydrazide to amino — .4-2- — 1968 and, if desired, converting a free base obtained irtto an 1 acid-addition salt thereof. claim 7 or 8, which comprises reacting a di-(lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioate with a hydrazine salt of the formula R-NHNH »nH An to produce a compound ^ x where R' is lower-carbalkoxy, wherein n is 1 or 2, x is 1, 2 or 3 and An is an anion of a strong inorganic acid or an organic sulphonic acid, if desired, reacting . „ said compound obtained where R' is lower-carbalkoxy with hydrazine hydrate or anhydrous hydrazine to produce a compound where R' is aminocarbamyl, if desired, reacting a compound obtained where R' is lower-carbalkoxy with ammonia to obtain the compound where R1 is carbamyl or hydrolyzing a compound obtained where R' is lower-carbalkoxy to obtain the compound where R' is carboxy, and, if desired, reacting a compound obtained where R' is carboxy with a chlorinating agent to form an acid chloride and reacting said acid chloride with ammonia to form a compound where R' is carbamyl, and, if desired, converting a free base obtained into an acid-addition salt thereof. 13. A cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically-acceptable inert carrier and, as the active component thereof, an effective amount of a cardiotonic compound or pharmaceutically-acceptable acid-addition salt thereof according to any one of claims 1-8, where R' does not include carboxy, and R does not include hydrogen when R' is lower-carbalkoxy. 14. A process for preparing a compound according to claim 1, substantially as herein described with reference to any of the Exairples C.l-17, D.l-16, E.l-16, f.l-16, and G.l-61. 15. A compound when prepared by a process according to any one of claims 11, 12 and 14. 16. A compound according to claim 1, or a cardiotonic coirposition comprising same substantially as herein described with reference to the Exairples 0.1-17,0.1-16, e.

1. -16, F.l-16, and G.l-61. 12. A process for preparing a compound according to By fcttS/thelr authorised Agents., A. J. PARK & SON.