PYRIDONE ESTERS AS INOTROPIC AGENTS

Abstract: Compounds of formula (I) wherein R is hydrogen, lower alkyl, halo, cyano, hydroxy, amino, lower alkylamino, -CH2NH2, -CH2OH or -COOR''; R' is hydrogen, lower cycloalkyl or lower alkyl; R'' is lower alkenyl, lower alkynyl, lower cycloalkyl, -(W)nY wherein W is straight or branched chain lower alkyl or lower alkenyl, n is 0 to 5, and Y is Ar, lower cycloalkyl, lower alkenyl, lower alkynyl, -COOZ wherein Z is lower alkyl, a compound of formula (II), or NAB wherein A and B are, independently, lower alkyl, benzyl or substituted benzyl, and Ar is 2, 3 or 4-pyridyl, pyridazinyl, pyrimidinyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, thiazolyl, phenyl, benzyl, furyl, tetrahydrofuryl or thienyl, unsubstituted or substituted with lower alkyl, lower alkoxy, halo, amino, or -CF3; R''' is -COOR'', a compound of formulas (III) and X is oxygen or nitrogen; or a pharmaceutically acceptable salt thereof, and their use in the treatment of impaired ventricular myocardial contractility. The compounds exhibit cardiotonic activity.

Description: 1 PYRJDONE ESTERS AS INOTROPIC AGENTS BACKGROUND OF THE INVENTION Cardlotonlc agents have been used for the treatment of heart failure for some time with digital Is continuing to be one of the principle phaππa- coIogle agents used for this purpose, although the cardiac glycosIdes as a class do have some limitations. Cardiac output Is regulated by the Inte¬ gration of the contractile state of the heart and the dynamics of the peripheral circulatory system. When the heart falls, the primary problem Is Impairment of ventricular myocardlal contractility which results In Inadequate cardiac output to meet the metabol Ic and circulatory demands of the body. Effective therapy of heart failure Is accomplished by either enhancing the contractile state of the heart with positive Ino roplc agents, or by adjusting the peripheral circulatory state with peripheral vasodilators. Agents which stimulate myocardlal contractility are of considerable value In the treatment of heart failure. Conventional therapy for heart failure has been the use of digitalis preparations-which are the only orally effective Inotroplc drugs available for use In the treatment of this condition. However, their peripheral vascular effects are undesir¬ able. Sympathomlmetlc amines are the other major class of cardiac stimulants which are used for the treatment of heart failure. The use of these agents Is likewise limited, because they are not fully effective when administered orally and because of undesirable peripheral vasoconstrictor action. Currently, dobutamlne and dopamlne are the sympathomlmetlc agents which are primarily used for heart failure, but they can only be admlnl- stered parenteral ly. Several premising Inotroplc agents which have been studied clinically are the pyrldones, amrfnone and mlIrfnone, having the following formula: A rlnone: lrlnone: Rj»CH3; R2«CN Amrlnone Is effective In treating patients with heart failure but Its use has been severely restricted to acute use only because It has been associated with a high Incidence of serious side effects. Mllrlnone Is undergoing clinical testing as an Inotroplc agent and Its usefulness has not yet been establ tshed. Because of the limitations of currently available drugs In the treatment of heart failure, there ts a clear need for new, effective and safe drugs of this type. SUMMARY OF THE INVENTION The present Invention Is directed to compounds of the formula wherein R Is hydrogen, lower al yl, halo, cyano, hydroxy, amino lower a Iky I am I no, -CH2NH2* -Φ OH or -COOR"; R' Is hydrogen, lower cycloalkyl or lower alkyl; R n Is lower alkenyl, lower alkynyl, lower cycloalkyl, -<W) n Y wherein W Is straight or branched chain loweralkyl or lower alkenyl, n Is 0 to 5, and Y Is Ar, lower cycloalkyl, lower alkenyl, lower alkynyl, -COOZ wherein Z Is lower alkyl, r I , or NAB wherein A and B are, Independently, lower alkyl, benzyl or substituted benzyl, and Ar Is 2, 3 or 4-pyrIdyl, pyrldazlnyl, pyrlmldlnyl, quinolyl, Isoquinolyl, phthalazinyl, quinazolinyl, thiazolyl, phenyl, benzyl, furyl, tetrahydrofuryl or thienyl, unsubstituted or substituted with lower alkyl, lower alkoxy, halo, a ino, or -CF 3 ; R , Is -C00R M , and; X Is oxygen or nitrogen; or a pharmaceutically acceptable salt thereof, and their use In the treatment of cardiac disorders, and In particular, In providing a positive Inotroplc effect In the treatment of Impaired ventricular myocardIaI contract111ty. The term "lower alkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms Including but not limited to methyl, ethyl, n-propyl, Iso-propyl, n-butyl, sec-butyl, 2-methyIhβxyI, n-pentyl, 1-methyIbutyI, 2,2-dlmethyIbutyl, 2-methyI entyl, 2,2-dlmethyIpropyI, n-hexyl and the like. The term "lower cycloalkyl" as used herein refers to cyclic saturated aliphatic radicals containing 3 to 6 carbon atoms In the ring, such as cγclopropγl, cγclobutyl, cyciopentyl or cyclohexyl. The term "halo" Includes chloro, fluoro, bromo and lodo. The term "substituted phenyl" represents phenγl which may be substituted with lower alkyl, halo, hydroxγ, alkoxy or amino. The term "pharmaceutically acceptable salts" Includes nontoxlc acid addition salts of the compounds of the Invention which are generally prepared by reacting the free base with a suitable organic or Inorganic acid. Representative salts Include the hydrochlorlde, hydrobromlde, sulfate, btsulfate, acetate, oxalate, valerate, oleate, palmltate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succlnate, tartrate, and I Ike salts. Also Included are metallic salts such as the sodium or potassium salt of the acid. The present compounds may be administered to warm-blooded animals orally or parenteral ly. They can generally be administered with a pharma¬ ceutical carrier. The term "pharmaceutical carrier," for the purpose of the present Invention, Is Intended to refer to any medium that Is suitable for the preparation of a dosage unit form, and, thus. Includes the tablet medium or a pharmaceuticalγ acceptable vehicle or solvent such as Is ordinarily used In the preparation of Intravenous or Intramuscular solutions. A pharmaceutical composition containing the compound can be administered to warm-blooded animals In parenteral or oral dosage form. For parenteral administration, amounts of fr m about 10 to 100 mg/kg per day per patient are useful, with the total dose of up to 0.2 to 2 grams per day being a suitable range for large animals, Including humans. A pre¬ ferred dosage range Is from about 1 to 10 grams total dally dosage In a single or.divided dose. For al I dosage forms the above exempt Ifled compounds can be placed In capsules, formulated Into pills, wafers, or tablets In conventional fashion together with pharmaceutical carriers well known In the art. Tablets may be prepared for Immediate release of the active compound or they may be made enteric, I.e., whereby ' the active Ingredient Is released slowly over a period of several hours from within the Intestinal tract. DETAILED DESCRIPTION OF THE INVENTION In order to Illustrate the manner In which the above compounds may be prepared and the properties of the compounds, reference Is made to the following examples, which, however, are not meant to limit or restrict the scope of the Invention In any respect. In the following examples, melting points were obtained on a Thomas-Hoover melting point apparatus and are uncorrected. NMR spectra were obtained on a Varlan T-60A spectrometer. IR spectra were obtained on a Perkfn-Elmer 283 spectrometer. Examples 1 through 5 describe the preparation of Intermediates: EXAMPLE 1 EthyI ethoxymethyIeneacetoacetate (1): Using the procedure of Crcmbfe et al., Jsai∑Jϊ * Sii £hsm. JSoς. PerkIn Jeans.1, 464-471 (1979), a solution of ethyl acetoacetate (26 g, 0.20 mol), trIethyI orthoformate (29.6 g, 0.20 mol) and acetic anhydride (41 g, 0.40 mol) was refluxed for 90 minutes. Distillation under reduced pressure gave the product (1): 26 g, 70$ yield; bp « 85-98* C at 0.5 mm Hg (The following value Is reported In the Crcmble et al. publication: bp * 85° C at 0.25 mm Hg); NMR (CDCI3) 6 1.2-1.5 (m ,6H), 2.4-2.5 (d,3H), 4.0-4.6 ( m,4H), 7.7 (d,1H). The signals were split Into pairs of closely spaced lines Indicative of the els and trans Isomers. Using the method of Example 1, the following Intermediates were prepared. EXAMPLE 2 MethyI methoxymethyIeneacetoacetate ( ): From methyl aceto- acetate (30.2 g, 0.26 mol), trlmethyl orthofor ate (26.7 g, 0.18 mol) and acetic anhydride (53 g., 0.52 mol): 4.3 g, 15* bp = 100-105* C at 0.5 mm Hg (lit. 1 80-84* C at 0.15 mm Hg); NMR (CDCI3) $ 2.4 (d, 3H), 3.8 (d, 3H), 4.1 (s, 3H), 7.6 (d, 1H). EXAMPLE 3 IsopropyI ethoxymethyIeneacetoacetate (£): From Isopropyl acetoacetate (28.8 g, 0.20 mol) which can be made by the process described by Lawesson et al., Organic Synthesis,. Coll. Vol. V r 155-157 (1973), trlethyl orthoformate (29.6 g, 0.20 mol) and acetic anhydride (41 g, 0.40 mol): 14.3 g, 35.7J; bp = 85-90° C at 0.20 mm Hg; NMR (CDCI3) δ 1.3-1.6 (m, 9H), 2.3-2.6 (d, 3H), 4.1-4.5 (m, 2H), 5.0-5.4 (m, 1H), 7.6-7.8 (d, 1H). EXAMPLE 4 BenzyI ethoxymethyI neacetoacetate (4): From benzyl acetoacetate (38.4 g, 0.20 mol), trlethyl orthoformate (29.6 g, 0.20 mol) and acetic anhydride (41 g, 0.40 mol): 10.7 g, 21.5$; bp * 170-183* C at 0.5 mm Hg; NMR (CXI3) δ 1.0-1.4 (t, 3H), 2.2-2.3 (d, 3H), 4.0-4.4 (q, 2H), 5.2 (d, 2H), 7.4 (s, 5H), 7.8-8.0 (d, 1H). EXAMPLE 5 Ethoxymethy1 neacety1acetone (£): From acβtyIacetone (20 g, 0.20 mol), trlethyl orthoformate (29.6 g, 0.20 mol) and acetic anhydride (41 g, 0.40 mol): 19.3 g, 62J; bp « 95-110* C at 0.3 mm Hg; NMR (CDCI3) δ 1.3-1.6 (t, 3H), 2.4 (d, 6H), 4.3-4.5 (q, 2H), 7.8 (d, 1H). EXAMPLE 6 EthyI 3-cyanc-β-methyl-2-pyrIdoπe-5-carboxyIate (&): Following the procedure described by Sunthankar et al., Indian JOJJΓJI. St Jisffl. _LL (12), 1315-1316 (1973), to a solution of sodium metal (2.3 g, 0.1 g-atom) In ethanol (50 mi) was added slowly with stirring an ethanollc solution (200 mi) of cyanoacetamlde (8.4 g, 0.1 mol). The reaction mixture was stirred for about 5 minutes, after which an ethanollc solution (20 mi) of compound 1.(18.6 g, 0.1 mol) was added. The mixture was stirred for 10 minutes during which time It became turbid, yellow and warm. The mixture was refluxed for 45 minutes. Ethanol was then removed under reduced pressure leaving the γel low sodium salt residue. This was dissolved In 50 ml water (with heating) and acidified with 6U HCi to pH 2-3 In an Ice bath. The off-white solids that precipitated out were filtered and washed with cold water until the filtrate was no longer acidic. The cycl Izatlon was done by refluxlng the solids In 600 ml of 95* ethanol for two hours. After cooling to room temperature for 18 hours, white crystals precipitated out. These were filtered and washed with cold ethanol. More of the product was obtained by concentrating the filtrate under reduced pressure. A total of 11.5 g (56* yield) was obtained: mp * 214-216° C; NMR (DMS0-d 6 ) δ 1.3-1.5 (t, 3H), 2.7 (s, 3H), 3.2-3.3 (NH), 4.1-4.5 (q, 2H), 8.5 (s, 1H); IR (KBr) 2220 cnrϊ(CN), 1640-1710 cm' 1 (C » 0 of pyrldone and ester). The following compounds were prepared In a manner similar to that described In Example 6. EXAMPLE 7 Methy I 3-cy ano-6-methy I -2-py r 1 dono-S-carhoxy I ate (2) : From cyanoacetamlde (0.02 mol ) , sod i um metal (0.02 g-atom) In MeOH (20 ml ) and 2 (0.02 mol ) : 0.8 g, 21* yiel d; mp=281-283 β C (decomposed) ; NMR (DMS0-d 6 ) δ 2.6 (s, 3H) , 3.2 (NH, OH) , 3.8 (s, 3H) , 8.4 (s, 1 H) ; IR (KBr) 2220 cm" 1 (CN) , 1650 cm" 1 (C=0 of pyrl done) , 1700-1720 on" 1 (00 of ester) . EXAMPLE 8 \sopropyI 3-cyano-6-methyl-2-pyrldono-5-carboxyIate (fi): From cyanoacetamlde (0.032 mol), sodium Isopropoxlde (0.032 mol) and (0.032 mol): 1.3 g, 18* yield; mp « 237-8* C; NMR (DMS0-d 6 ) δ 1.2-1.4 (2s, 6H), 2.6 (s, 3H), 3.2-3.4 (NH), 4.8-5.2 (m, 1H), 8.4 (s, 1H); IR (KBr) 2220 cm" 1 (CN), 1660 cm' 1 (00 of pyrldone), 1700 cm" 1 (C=0 of ester). The NMR showed presence of approximately 20-25* of the compound of Example 6. EXAMPLE 9 n-Buty I 3-ςyaπo-6-methy l-2-pyr I dpπeτ5_-carbgχy | ate (≤) : mp 183-185* C EXAMPLE 10 sec-ButyI 3-cyaπo-6-methyl-2-pyr1done-5-carboxyIate (IQ) : p 228.8* C EXAMPLE 11 IsobutyI 3-cyano-6-methyI-2-pyr1done-5-carboxy1ate (J ): p 192.9* C (decomposed) EXAMPLE 12 IsopentyI 3-cyano-6-me hy1-2-pyr1done-5-carboxyIate (J2): p 203.2* C (decomposed) EXAMPLE 13 n-Octy 1 3-cyano-6-methy l-2-pyrldone-5-carboxy 1 ate (J2) : mp 162.9* C I EXAMPLE 14 CyeIopentyI 3-cyano-6-methyI-2-py 1 one-5-carboxyIate (l±): mp 248.4* C (decomposed) EXAMPLE 15 CyelohexyI 3-cyanc-6-methyI-2-pyrIdone-5-carboxyIate (J5.): mp 233.8* C (decomposed) EXAMPLE 16 Cye1o ropyfmethy1 3-cyanc-6-methyI-2-pyrIdone-5-carboxyIate (J£): mp 203.6* C (decomposed) EXAMPLE 17 Cye1ohexy1methyI 3-cyano-6-methyI-2-pyrIdone-5-carboxyI a β (17 : mp 235.1* C (decomposed) EXAMPLE 18 2 Furytmethy 3-cyano-6-methyl-2-pyrIdone-5-carboxylate (Jfi) : mp 191.2* C (decomposed) EXAMPLE 19 (3-Methyl )-benzy l 3-cyano-6-methy l-2-pyr Idone-5-carboxy t ate (JS : mp 213* C (decomposed) EXAMPLE 20 (4-T 1fIuoromethyI)benzyI 3-cyano-6-methyI-2-pyr1done-5-carboxy \ate (2tt): mp 221.2* C EXAMPLE 21 5-Acetyl-3-cyaπo-6-methy l-2-pyrIdone (21) : From cyanoacetamlde (0.02 mol ) , sodi um metal (0.02 g-atom) In MeOH ( 10 ml ) , and (0.02 mol ) : 1 .0 g, 28* yiel d; mp * 233-4* C; NMR (DMS0-d 6 ) δ 2.5 (s, 3H) , 2.6 (s, 3H ) , 8.8 (s, 1 H) ; IR (KBr), 1660 cm" 1 (00 of pyrldone) , 1690 cm" 1 (C=0 of ketone) . EXAMPlrE 22 BenzyI 3-cyaπo-6-methy1-2-pyrldone-5-carboxyIate ( 22 ) : Using the method described by Hawaldar et al., Indian JIΩUΓJ.. SΪ CJϋam., Jissϊ. J3, 123 (2), 151-152 (1980) a mixture of compound 1 (2.5 g, 0.01 mol), cyanoacetamlde (0.84 g, 0..01 mol), trlethylbenzyIammonium chloride (TEBA, 1.1 g 0.005 mol) and 50* NaOH solution (2 ml) was stirred for about 4 hours. The reaction was exothermic and became bright orange. The Initially clear solution Immediately solidified. A small amount of water was added to facilitate stirring. The mixture was then acidified with 6ϋ HCI, the solids filtered and washed with water and methanol (MeOH) successively. A total of 0.94 g (35*) of off-white solids was obtained: mp « 265-270* C; NMR (DMS0-d 6 ) δ 2.6 (s, 3H), 3.2-3.5 (NH), 5.4 (s, 2H), 7.4 (s, 5H), 8.6 (s, 1H); IR (KBr) 2240 cm *1 (CN), 1660 on" 1 (00 of pyrldone), 1730 cm" 1 (C*0 of ester). EXAMPLE 23 3-Cyano-6-methyl-2-pyι-!done-5-carboxyl Ic acid (22): This compound was synthesized In the same manner as the compound of Example 22 from cyanoacetamlde (0.01 mol), TEBA (0.005 mol), 1 (0.01 mol) and 50* NaOH solution ( 2 ml ) . A more efficient method of preparing this compound was refluxlng the compound 6 (0.3 g, 1.5 mmol ) with NaOH solution (1 ml, 50*) for 1 hour. White solids precipitated out when the solution was acidified with 6H HCI to pH » 1. These solids were filtered, washed thoroughly with water and dried to give 0.24 g (90* yield) of the product: mp « 285-287* C 11 with decomposition; NMR (DMSO-dβ) δ 2.6 (s, 3H), 8.4 (s, 1H); IR (KBr) 2220 cm" 1 (CN), 1640-1660 cm" 1 (00 of pyrldone), 1710 cm" 1 (C=0 of carboxyl Ic acid). EXAMPLE 24 3-fMethoxycarbonyl )-5-(ethoxycarbonyl)-6-methy l-2-pyrone ( a) and 5- (Methoxycarbon 1-5- ( ethoxycarbony I )-6-methy I -2-py r I done (24l): Using the procedure described by Baker et al., Jourr. jo± CJiejD..Sac. Par in Trans.1, 3_, 677-685 (1979), ethyl cyanoacetate (3.5 g, 0.031 mol) was added to NaOMe solution (prepared from 0.72 g of sodium metal In 50 ml of MeOH), followed by 1 (5.77 g, 0.031 mol). The mixture was ref luxed for 15 minutes, cooled and divided Into two equal parts. The first portion was acidified with 2N HCI to pH 2-3 and extracted with £ CH2Cl2« The extracts were washed, dried over MgS04, and evaporated to • _ give an orange-colored solid. After decolorizing with Nuchar activated carbon In ethyl acetate and recrystal I Izlng from EtOAc-hexane, white, fluffy crystals, of 3-(methoxycarbony I) -5- (ethoxycarbony l)-6-methy I- 2-pyrone were obtained: 0.22 g, 6* yield; mp « 94-96* C; NMR (DMSO-ds) δ 1.2-1.5 (t, 3H), 2.7 (s, 3H), 3.8 (s, 3H), 4.1-4.6 (q, 2H), 8.5 (s, 1H); IR (KBr) 1700-1730 cm" 1 (00 of Me and Et ester), 1770 cm" 1 (00 of pyrone). The second portion was treated with glacial acetic acid (0.8 ml) and refluxed for 2 hours. Seme solids which formed during the reaction were filtered off. The filtrate was acidified with 6N HCI to pH - 1-2, precipitating out the desired pyrldone as an orange solid. Purification 5 of this solid with Nuchar activated carbon and recrystal I Izatlon from MeOH-ether gave white, fluffy crystals of 3-(methoxycarbonyl -5- (ethoxycarbonyl)-6-methyl-2-pyrldone: 0.15 g, 4* yield; mp * 200-202* C; NMR (DMS0-d 6 ) δ 1.2-1.5 (t, 3H), 2.6 (s, 3H), 3.8 (s, 3H), 4.1-4.4 (q, 2H), 8.6 (s, 1H); IR (KBr) 1660 cm" 1 (00 of pyrldone), 1700-1710 0 cm" 1 (C=0 of ester). 12 EXAMPLE 25 3.5-Bls-ethoxycarbonyl-6-methyl-2-pyrIdone (25.): Ethyl- cγanoacetate (2.26 g, 0.02 mol) was added to a NaOEt solution (prepared from 0.46 g of sodium metal In 50 ml EtOH), fol lowed by compound 1 (3.72 g, 0.02 mol). The solution was ref luxed for 12 hours. Shiny, light- yellow crystals precipitated out after 18 hours of standing at room temperature. After decolorizing with Nuchar activated carbon, white crystals of 3,5-bfs-βthoxycarbony I-6-methy 1-2-pyrIdone were obtained: 1.45 g, 29* yield; mp * 195-197* C; NMR (DMSO-de) δ 1.1-1.5 (t, 6H), 2.6 (s, 3H), 4.1-4.5 (q, 4H), 8.6 (s, 1H), 12.6 (NH); IR (KBr) 1660 cm" 1 (C=0 of pyrldone), 1700 cm" 1 and 1720 cm" 1 (C=0 of ester). EXAMPLE 26 EthyI 3-cyano-6-methyl-2-pyrIdone-4-carboxyIate (26 : Based on the method described by Fuchs et al., £hssi. £ksi», 11, 100533 f (1970), a solution of sodium metal (1.15 g, 0.05 g-atcm) In ethanol (32 ml) was added to acetone (2.9 g, 0.05 mol) and dlethyloxalate (7.31 g, 0.05 mol) In ethanol (10 ml), followed by cyanoacetamlde (2.77 g, 0.033 mol) In water (15 ml). The solution was heated on an oil bath at 60-70* C for 30 minutes with constant stirring. The solvent was removed under reduced pressure giving an orange solid which was dissolved In a small amount of water and acidified with 6N HCI to pH * 2, giving a yel low solid. After filtering and drying, a crude yield of 5.4 g (79*) was obtained. Decolorizing with Nuchar activated carbon gave light-yellow, needlel Ike crystals: 2.52 g, 24* yield; mp « 215-217* C; NMR (DMSO-dδ) 1.2-1.5 (t, 3H), 2.4 (s, 1H), 4.2-4.6 (q, 2H), 6.6 (s, 1H); IR (KBr) 2240 cm" 1 (CN), 1640 cm" 1 (00 of pyrldone), 1720 cm" 1 (00 of ester). EXAMPLE 27 3- ( N-lmldazolyl-carbonyn-6-methyl-2-pyrIdone (22) : To 4 g (0.026 mol) of 6-methyl-2-pyrIdone-3-carboxyl Ic acid In 25 mi DMF was added 5.3 g (0.033 mol) of carbonyldl fmldazole. The mixture was heated to 55* C with stirring for 2.5 hours. Bubbles and off-white precipitate were observed during this period. After filtering the solids, washing thoroughly with THF and drying in the vacuum desslcator for 18 hours, 4.7 g (89*) of the product was obtained: mp « 237-239* C with decomposition; NMR (DMSOd 6 ) δ 2.3 (s, 3H), 3.4 (NH), 6.2-6.4 (d, 1H), 7.1 (d, 1H), 7.6 (d, 1H), 7.8-8.0 (d, 1H), 8.2 (d, 1H); IR (KBr) 1660 cm" 1 (00), 1700 cm" 1 (00). EXAMPLE 28 5-(-N- lmldazolyl-carbonyl )-2-pyrldone (28 : 6-Hydroxy-nIcotI nIc aci d (8.0 g, 0.06 mol ) and carbony l dl Imldazol e (12.0 g, 0.074 mol ) were heated at 55* C for 4 hours I n 50 ml DMF. After f i l tering and wash ing w ith ether and water, l lght-befge crystal s of product were obtained: 4.2 g, 38* yiel d; mp = 200-200.5° C; NMR (DMSO-dg ) δ 6.4 (d, 1 H) , 7.2 (s, 1 H) , 7.6-8.1 (m, 3H) , 8.4 (s, 1 H) ; IR (KBr) 1600 cm" 1 , 1650-1680 cm" 1 (C=0 of pyrldone and Imldazol Ide) . EXAMPLE 29 5-(-N-lmldazolyl-carbonyn-3-cyano-6-methyl-2-pyrIdone (22): To 0.20 g (1.1 mmol) of 11 In 10 ml DMF was added carbonyIdI Imldazole (0.223 g, 1.4 mmol). The solution was stirred for 24 hours at room temperature. DImethyiformamfde was stripped off under reduced pressure giving an oil which crystallized upon further drying. The solid was washed with water and dried In the vacuum desslcator. Yellow solids were obtained: 0.11 g, 40* yield; mp « 237-238* C with decomposition; NMR ( DMSO-dg ) δ 2.5 (s, 3H), 7.2 (d, 1H), 7.8 (d, 1H), 8.4 (2s, 2H); IR ( KBr ) 1670 cm" 1 ( CO of pyrldone), 1710 cm" 1 (00 of Imldazoilde). EXAMPLE 30 5-(4 r 4-DImathyl-2-oxazolln-2- l)-2-pyrldone (3JD : 2-Methyl-2-amIno-1-propanol (0.94 g, 0.011 mol) and compound 22 (2.0 g, 0.011 mol) were ref luxed for 12 hours In 100 ml DMF. The solvent was stripped off giving an oil which was washed with ether and CH2CI2 and further dried under reduced pressure. Thlonyl chloride (10 ml) was then added to the oil and the mixture stirred for 30 minutes. The thlonyl chloride suspension was added dropwise to 100 ml of 15* NaOH, cooled In an Ice-bath, and more base was added until pH reached 7-8. Insoluble materials were filtered off. The filtrate was extracted with CH2CI2 (2x 50 ml) and the organic extract was separated out, dried over MgS04 and concentrated to an oil, which crystallized on standing. Trlturatlon with EtOAc removed the yellow color and gave 0.49 g (23* yield) of white crystalline solid: mp - 172-173* C; NMR (DMS0-d 6 ) δ 1.4 (s, 6H), 4.0 (s, 2H), 6.5-6.7 (d, 1H), 8.0-8.2 (m, 2H); IR (KBr) 1600 cnT 1 , 1650-1680 cm" 1 (C=0 of pyrldone and ON). EXAMPLE 31 Ethyl 2-pyrldone-5-carboxylate (21): To 6-hydroxynlcotlnlc acid (1.0 g, 7.19 mmol) suspended In absolute ethanol (EtOH) (10ml) was added dropwise SOCI2 (0.55 ml, 7.5 mmol). The reaction mixture was warmed at reflux for 4 hours and concentrated under reduced pressure. The white solid obtained was stirred In hexanes, filtered, and dried to give the product as the hydrochlorlde salt (1.38 g, 94*), mp ■ 117-124* C, NMR ( DMS0-d 6 ) δ 1.45 (t, J « 7Hz, 3H), 4.27 (q, J - 7Hz, 2H), 6.35-8.17 (m, 3H). Employing the above described procedure and starting with the appropriate alcohol, the following compounds were prepared. EXAMPLE 32 Methyl 2-pyrIdone-5-carboxylate (22): p 169-170*C; NMR ( DMS0-d 6 ) δ 3.8 (s,3H), 6.45 (d, 1H), 7.91 (m, 2H). EXAMPLE 33 I sopropy I 2-py r I done-5-carboxy I ate (22) : mp 123-127°C; NMR (DMS0-d 6 ) δ 1 .29 (d, ,6H) , 5.07 (bm, 1 H) , 6.38 (d, 1 H) , 7.87 (m, 2H) . EXAMPLE 34 Ethy13-cyano-5 r 6-dImethy1-2-pyrldone-4-carboxyIate (24): Using the method of Example 26, a solution of NaOEt was prepared by dissolving sodium (1.15 g, 50 mmol) in absolute EtOH (50 ml). This solution plus an EtOH (2 ml) wash was added to a solution of methylethyl ketone (4.5 ml, 50 mmol) and diethyl oxalate (6.8 ml, 50 mmol) In EtOH (15 ml). A solution of cyanoacetamlde (2.77 g, 33 mmol) in water (15 ml) was added and the reaction mixture warmed at 65* C for 35 minutes. The reaction mixture was concentrated under reduced pressure, taken up in H2O (250 ml), filtered, and the filtrate acidified with 6_B HCI. Filtration afforded a mixture of the 5,6-dlmethyl and 6-ethyl compounds. From the filtrate the product crystallized (400 mg, 6*) as a bright yellow solid, mp - 172-176* C, NMR (DMS0-d 6 ) δ 1.33 (t, J » 7Hz, 3H), 1.92 (s, 3H), 2.33 (s, 3H), 4.42 (q, J • 7Hz, 2H), IR (KBr) 2230, 1740, 1650 cm" 1 . Employing the procedure of Example 22 and starting with the appropriate ketone, oxalate, aikoxlde, and alcohol, the following compounds were prepared. EXAMPLE 35 EthyI 3-cyano-6-cyclopropy1-2-pyrldone-4-carboxy1ate (22): mp 210-212*C; NMR (DMS0-d 6 ) δ 1.33 (+, J-7H 2 , 3H), 1.17 (m, 4H), 2.01 (m, tH), 4.38 (q, J-7Hz, 2 H), 6.35 (s, 1H); IR (KBr) 2230, 1725, 1640 an" 1 . EXAMPLE 36 Methy 1 3-cyano-6-methy I -2-py r I done-4-carhoxy I ate (26.) : mp 233-234*C; NMR (DMS0-D 6 ) δ 2.35 (s, 3H) , 3.92 (s, 3H) , 6.58 (s, 1 H) ; IR CKBr) 2230, 1740, 1670 cm" 1 . EXAMPLE 37 Isopropy i 3-cyano-6-methy I-2-pyrldone-4-carboxy l ate (22) : mp 216.9*C (dec) ; NMR (DMS0-d 6 ) « 1 .33 (d, J=6H 2 , 6H) , 2.33 (s, 3H) , s.15 (m, 1 H) , 6.50 (s, 1 H) ; IR (KBr) 2230, 1735, 1650 cm" 1 . EXAMPLE 38 sec-ButyI 3-cyano-6-methyl-2-pyrIdone-4-carboxyIate (2&): p 158.7* C The described compounds are active Inotroplc or cardlotonlc agents. They have been found to Increase the contractile force of the heart while having mlntmal effects on bl od pressure and heart rate and can be used In treating patients with diseased hearts for the purpose of Increasing cardiac efficiency through a selective Increase In the cardiac contractile force. The cardlotonlc activity of the compounds was established using the fo lowing test procedure: Male Hartley strain guinea pigs (250-500 g body weight), obtained from Hilltop Lab Animals (Scottdale, PA), were stunned by a blow to the head and the left atria removed and rinsed In a modified Kreb's-Henselelt buffer. The buffer was continuously gassed with 95* oxygen and 5* carbon dioxide and was composed of the following: NaCI, 118 mM; KCl, 4.7 mM; MgS0 4 , 1.2 mM; KH 2 P0 , 1.2 raM; CaCl 2 , 1.25 mM; NaHC0 3 , 25 mM; Nβ2EDTA, 0.03 mM and D-glucose, 11 mM. The left atria were pierced through one end of the atrlal appendage by a platinum hook connected to a fine gold chain and pierced at the other end of the appendage by a partially shielded platinum hook fixed to a glass rod. The glass rod and atrium were suspended In a 30 ml water-Jacketed tissue bath containing the Kreb's buffer at 33* C. Also connected to the glass rod was a second shielded platinum wire which was adjusted so that a 3-5 mm length of an unshielded portion of the wire was In contact with the atrium very near to the first shielded wire. Both platinum wires were connected to a Grass CCU1A constant current unit and a current was appl led by a Grass S44 stimulator to drive the atrium by means of "point" stimulation. The parameters of stimulation were 1-3 mAmps, 1.5 Hz and 5 msec pulse duration. Each tissue was stretched to an Initial resting tension of 1.0 g without further readjustment and washed periodically with fresh Kreb τ s buffer over a one-hour Interval. Developed tension was measured from a Statham UC-3 force transducer connected to the gold chain and recorded on a Gould 2800S recorder. The force signal was also passed to the A/D converter of a MINC-23 computer where the force signal was derlvatlzed to calculate several characteristics of the contractile wave-form. After the one-hour equilibration period, test compounds were added cumulatively to the bath In small volumes (10-100 ul) at 10-mlnute Intervals beginning at concentrations of 10" M and Increasing by log or 1/2 log units until a concentration of 3 x 10"^ M was reached. Using the described procedure, the change In tension In milligrams is measured. An Increase In tension Indicates a greater contractile force. The Increase In tension produced by several representative compounds Is recorded In the following table In which ED20 represents the dose of the compound which causes a 20* Increase In contractile force; GPLA Is "guinea pig left atrium"; and IA Is the intrinsic activity as contractile force In comparison to Isoproterenol (1). LE GPLA 1 NH H H 5-C0 2 Et 1285 0.50 2 NH H H 5-Cθ2Me 1250 0.42 3 NH H H 5-Cθ2- l-Pr 137 0.80 4 NH CN Iτβ 5-C0 Et 39 0.80* 24 0.63 + 5 NH CN MΘ 5-C0 2 Me 427 0.50 + 6 NH CN Me 5-C0 CH 2 Ph 11 0.48* 7 NH CN Me 5-∞2-l-Pr 15 0.60* 8 NH CN Mβ 5-CO-N. N 45 0.92* 9 NH CO- N N rτ6 H 180 1 .0* 10 NH C0 2 Et Me 5-C0 2 Et 130 0.40* 11 NH C0 2 θ l*to 5-∞2Et 475 0.30« 12 NH H H 826 0.58* 13 NH H H 5-CO-N N 267 1 .12* 14 NH CN Me 4-C0 Et, 5-Me 116 0.84* 15 NH CN Flo 4-C0 2 Et 1209 0.51 * 16 0 C0 2 Θ Me 5-∞2Et 97 0.45* 17 NH CN Me 5-C02(CH 2 3CH3 18 0.45* * = Pre-treatment with Reserplne + = Pre-treatment with Propranolol TABLE 1 CONTINUED GPLA NH CN Mθ 5-C02 ( CH ) 7CH3 1207 0.5* NH CN Me 4-C0 2 Me 450 0.85* NH CN Me 4-C0 2 -l-Pr 649 0.6* NH CN Me 120 0.66* NH CN Me 28.5 0.41* 2Q EXAMPLE 39 Preparation of 8-keto-ester enamtnesi Using the procedure of Lesher at al . as described In U. S. Patent 4,297,360, a solution of the appropriate ester of acetoacetlc acid (0.05 mole) and dImethyI- formamlde dimethyl acetal (0.15 mole) was stirred at room temperature for 30 minutes to 2 hours. In some cases, refluxlng for 30 minutes to 1 hour was necessary to complete the reaction. Concentration under reduced pressure gave a yellow-orange or brown oily residue. Vacuum distillation of the crude residue gave a yellow oil as the desired product. For those keto-esters with a cycl ic, aromatic, or hetero- cycl Ic ring In the ester function, the crude oil was used without further purification since decomposlton of product was observed after vacuum distillation. 1 H-NMR analysis of the product showed the disappearance of the singlet peak at 3.4-3.6 ppm (2H) and the appearance of a sharp singlet at 7.6-7.8 ppm (1H) and a large singlet at 3.0-3.2 ppm (6H). The pyrldone esters were prepared as previously described using the enamlne In place of the analogous enol-ether. Employing this procedure, the follo ing compounds were prepared. Is) Ul Is) Ul Ul IS) K) vo 09 Ul o Is) v .o 0 .0 Ul Is) 8 ■ Ul o Ul Ul o α ?l ϊ + o o . l Ul ui σ» ui 4* Ul o κ» -j Ul K) VO o Ul ui -J 4k. l Ul OΛ OB ft * * * * 3 fc 4? H ? 4? II II II II i 4 I? ? I 4? ? H i H? II i I?I II H 3 .2 3 3 3 2l 2l U 2l , U2l 3 U 2l 3 u 2i H 5° + o o OI Ul R 3» Ul Ul fcs

Claims: 23 What Is claimed is: 1. A compound of the formula wherein R is hydrogen, lower alkyl, halo, cyano, hydroxy, amino, lower aIkyIamino, -CH2OH or -COOR"; R' Is hydrogen, lower cycloalkyl or 5 lower alkyl; R n Is lower alkenyl, lower alkynyl, lower cycloalkyl, -(W) n Y wherein W Is straight or branched chain lower alkyl or lower alkenyl, n Is 0 to 5, and Y Is Ar, lower cycloalkyl, lower alkenyl, lower alkynyl, -COOZ wherein Z Is lower alkyl, J "] , or NAB wherein 0 A and B are, Independently, lower alkyl, benzyl or substituted benzyl, and Ar Is 2, 3 or 4-pyrfdyl, pyrfdazlnyl, pyrlmtdlnyl, quinolyl, Isoquinolyl, phthalazinyl, quinazolinyl, thiazolyl, phenyl, benzyl, furyl, tetra¬ hydrofuryl or thienyl, unsubstituted or substituted with lower alkyl, lower alkoxy, halo, amino, or -CF3; R" r Is -COOR", and X Is oxygen or nitrogen with the proviso that when R"' Is -COOR", R cannot be hydrogen or cyano or a pharmaceutically acceptable salt thereof. 2. A compound of Claim 1 wherein X Is nitrogen. 3. A compound of Claim 2 wherein R Is lower alkyl or cyano and R*' Is Q -CH 2 Ar. 4. A compound of Claim 3 wherein R Is methyl or cyano and R Is • benzyI 11 I 5. A compound of Claim 1 wherein R Is cyano, R' IS lower alkyl, R Is - -CCOOOORR 11 '*,, aanndd RR IIs -(W) n Y wherein W Is lower alkenyl, n Is 1 to 3, and Y Is 2,3 or 4 pyrldyl 6. A compound of Claim 5 wherein R* Is methyl, W Is O * n Is 1, and Y Is 2 or 3 pyrldyl. 7. A method of treating or relieving the symptoms associated with Impaired ventricular myocardlal contractility In a patient by providing a positive Inotroplc effect comprising administering to a patient In need of such treatment a therapeutical ly effective amount of a compound of the formula wherein R Is hydrogen, lower alkyl, halo, cyano, hydroxy, amino, lower alky I am I no, -CH2 H2, -CH2OH or -COOR"; R f Is hydrogen, lower cycloalkyl or lower alkyl; R" Is lower alkenyl, lower alkynyl, lower cycloalkyl, -(W) n Y wherein W Is straight or branched chain lower alkyl or lower alkenyl, n is 0 to 5, and Y Is Ar, lower cycloalkyl, lower alkenyl, lower alkynyl, -COOZ wherein Z Is lower alkyl, J" "J , or NAB wherein « A and B are, Independently, lower alkyl, benzyl or substituted benzyl, and Ar Is 2, 3 or 4-pyrldyl, pyrldazlnyl, pyrlmldlnyl, quinolyl, Isoquinolyl, phthalazinyl, quinazolinyl, thiazolyl, phenyl, benzyl, furyl, tetrahydrofuryl or thienyl, unsubstituted or substituted with lower alkyl, lower alkoxy, halo, amino, or -CF3; R" f Is -COOR", • o-- - or •CO- N nd X Is nitrogen; with the proviso that when R MI Is -C00R , R' cannot be hydrogen or cyano, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 8. The method of Claim 7 wherein X Is nitrogen. 9. A method of treating or rel ievlng the symptoms associated with Impaired ventricular myocardlal contractility In a patient by providing a positive Inotroplc effect comprising administering to a patient In need of such treatment a therapeutical ly effective amount of a compound of the formula wherei n R Is lower al kyl , hal o, hydroxy, amino, lower al ky lamlno, -CH2 H2 or -CH2OH or -COOR"; R' IS hydrogen, lower cycl oal ky l or lower al ky l ; R Is -CH2Ar wherein Ar Is phenyl , substituted pheny l , furan or thlophene; and R , Is COOR" , or a pharmaceutically acceptable salt thereof. 10. The method of Claim 9 wherein R ,t tt Is -CO-N ^ vN. 11. A pharmaceutical composition, useful for the treatment of impaired ventricular myocardlal contractility by providing a positive Introplc effect, w ich comprises an effective amount of a compound of the formula 5:; wherein R Is hydrogen, lower alkyl, halo, cyano, hydroxy, amino, lower alkylamlno, -CH2NH2, -CH2OH or -COOR"; R» Is hydrogen, lower cycloalkyl or lower alkyl; R" is lower alkenyi, lower alkynyl, lower cycloalkyl, -(W) n Y wherein W Is straight or branched chain lower alkyl or lower alkenyl, n is 0 to 5, and Y Is Ar, lower cycloalkyl, lower alkenyl, lower alkynyl, -COOZ ID wherein Z Is lower alkyl, r I , or NAB wherein Q « A and B are, Independently, lower alkyl, benzyl or substituted benzyl, and Ar Is 2, 3 or 4-pyrIdyl, pyrldazlnyl, pyrlmldlnyl, quinolyl, Isoquinolyl, phthalazinyl, quinazolinyl, thiazolyl, phenyl, benzyl, furyl, 15 tetrahydrofuryl or thienyl, unsubstituted or substituted with lower alkyl, lower alkoxy, halo, amino, or -CF3; R" 1 Is -COOR", and X Is nitrogen or oxygen with the proviso that when R 1 " Is -COOR 11 , R cannot be hydrogen or cyano, or a pharmaceutically acceptable salt thereof, 0 and a pharmaceutically acceptable carrier. 12. A composition of Claim 11 wherein X Is nitrogen. 13. A composition of Claim 11 wherein R Is lower alkyl or cyano and R ,f is -CH 2 Ar. 27 14. A pharmaceutical composition, useful for the treatment of Impaired ventricular myocardlal contractility by providing a positive Inotroplc effect, which comprises an effective amount of a compound of the formula wherein R Is lower alkyl, halo, hydroxy, amino, lower alkylamlno, -CH2NH2, -CH2OH or -COOR"; R 1 Is hydrogen, lower cycloalkyl or lower alkyl; R' IS hydrogen, lower cycloalkyl or lower alkyl, R" Is lower alkenyl, lower alkynyl, lower cycloalkyl, -(W) n Y wherein W Is straight or branched chain lower alkyl or lower alkenyl, n Is 0 to 5, and Y Is Ar, lower cycloalkyl, lower alkenyl, lower alkynyl, -COOZ wherein Z Is lower alkyl, ■ r 1 , or NAB wherein A and B are, Independently, lower alkyl, benzyl or substituted benzyl, and Ar Is 2, 3 or 4-pyrIdyI, pyrldazlnyl, pyrl ldlnyl, quinolyl, Isoquinolyl, phthalazinyl, quinazolinyl, thiazolyl, phenyl, benzyl, furyl, tetrahydrofuryl or thienyl, unsubstituted or substituted with lower alkyl, lower alkoxy, halo, amino, or -CF3; and R" f Is -COOR" or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 15. A pharmaceutical composition, useful for the treatment of Impaired ventricular myocardlal contractility by providing a positive Inotroplc effect, which comprises a compound of the formula wherein R Is lower alkyl, halo, hydroxy, amino, lower alkylamlno, -CH2 H2 or CH2OH or C00R ; R* Is hydrogen, lower cycloalkyl or lower alkyl; R Is CH2Ar wherein Ar Is phenyl, substituted phenyl, furan or thlophene; and R , Is C00R ff or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Inventors: BARCELON-YANG CYNTHIA, STOUT DAVID M, YAMAMOTO DIANE M, BARCELON-YANG, CYNTHIA, STOUT, DAVID, M., YAMAMOTO, DIANE, M.
Applicants: AMERICAN HOSPITAL SUPPLY CORP, AMERICAN HOSPITAL SUPPLY CORPORATION
Application year: 1985
Main classification: C07D213
IPC codes: C07C45, C07C49, C07D213, C07D405, C07D413, C07D521