PYRIDONE-PYRIDYL-IMIDAZOLYL AND TRIAZOLYL COMPOUNDS AND THEIR USE AS CARDIOTONIC AGENTS

Abstract: Pyridone-pyridyl-imidazolyl and triazolyl compounds, including methods for increasing cardiac contractility, pharmaceutical compositions including the same and methods for the preparation thereof.

Description: PYRIDONE-PYRIDYL-IMIDAZO YL AND TRIAZOLYL COMPOUNDS AND THEIR USE AS CARDIOTONIC AGENTS Field of t e Invent ion This invent ion relates to novel imidazolyl and tr tazolyl compounds br idged to a pyr idonβ r ing through a pyr idyl moiety at the 2,5-posi t ions of the pyr idine ring. These compounds possess useful cardiotonic propert ies. This invent ion also relates to the use of said imidazolyl and tr iazolyl pyr idyl pyr idone compounds as cardiotonic agents for increasing cardiac contract i l i ty, which can be used, for example, for the treatment of congest ive heart fai lure. This invention further relates to ph rmaceutical composi t ions including these same imidazolyl and tr tazolyl py r i dy I -py r i one compounds and the processes for the preparat ion thereof . Congest i ve heart fai lure i s a I i β- t h r ea t en i ng condi t ion in whi ch myocardial contract i l i ty i s depressed so that the heart i s unable to adequately pump b lood. Normal pathologic sequelae include decreased cardiac output , venous pool ing, increased venous pressure, edema, increased heart size, increased myocardial wal l tension, and eventual ly cessat ion of contract i l i ty. Reported Developments Drugs which increase the tone of the heart muscle are descr ibed as having posi t ive inotropic act ivi ty and are charac er ized as cardiotonic agents . Digi tal i s glycosides have long been used to increase myocardial contracti l i ty and reverse the detrimental changes seen in congest ive heart fai lure. More recent ly, dopamine. dobuta ine, and a r inone have; been used to provide necessary inotropic support for i no isi i ing heart . Cardiotonic agents which are described as having posi tive inotropic act ivi ty include the 5-pyr idyl substituted pyr idones disclosed in U.S. Patent Noβ. : 4,004,012! 4, 072.746» , I 07 , 3 I 5 ι 4 , 137,233 J 4, 199,586; 4, 271 ,168 ! and 4, 107,315; in GB 2070606Aι and in PCT publ ished Appl . No. PCT/CH81 /00023. Other cardiotonic drugs include 2( 1H) -py r ϊ done compounds having a phβnyl r ing attached at the 5-posi t ion and which phenyl ring may further be substi tuted at the 3-or 4-posit ion of the phenyl r ing wi h a 1-imidazolyi group. These are disclosed in U.S. Patent No. 4,503,06! . Summary of the Invent ion The present invent ion relates to imidazolyl and tr iazolyl compounds br idged to a pyr idone r ing by a pyr idyl moiety at the. 2,5-positions of the pyridine r ing as described by general formula I . He βrβ i n : Hβt is imi dazo I - 1 -y I or I , 2 , 4- t r i a zo I - 1 -y I ι X i s -CH = N - or -N = CH -; R, and R c are H or alkyl ; and i 6 R. i s H, alkyl , alkoxyalkyl , hyd roxya I k y I , halo, cyano, carbamoyl , alkyl carbamoyl , formyl , a I k y I βnβami no or aminoi or a pharmace ical ly acceptable sal t thereof . I t has been found that compounds wi thin the scope of the present invent ion possess surpr ising and unexpected posi t ive inotropic act ivi ty wi th a surpr i si ngly high degree of select ivi ty for thei r effects on contract i le force v s . thei r effects on heart rate. Thi s invent ion relates al so to pharmaceut ical composi t ions which are effect ive in increasing cardiotonic contract i l i ty in hu^ar. i r ether :nlmc! : znd whi ch are useful for the treatment of cardiac fai lure such as congest ive heart fai lure. De t i I ed Descr ip ion Certain of the compounds encompassed wi th the scope of the present invent ion, and part icular ly, compounds of the above formula, may exi st in enol ic or tautomβr i c forms . Al l of such forms are considered as being included wi thin the scope of thi s invent ion. The compounds of thi s invent ion which have part icular usefulness as cardiotonic agents are descr ibed by formulae I I to V. wherein R and R Λ are as descr i ed above The compounds of this invent ion may be useful in the form of the free base, in the form of sal ts, and as a hydrate. Al l of such forms are considered as being wi thin the scope of thi s invent ion. As employed above and throughout the disclosure, the fol lowing terms, unless otherwise indicated, shal l be understood to have the fol lowing meanings: "Alkyl" means a saturated al iphatic hydrocarbon which may be ei ther straight- or branched-chained containing from about one to about 6 carbon atoms. Lowβr alkyl " means an alkyl group as above , having I to about 4 carbon atoms. "Alkyl carbamoyl ' means a carbamoyl group subst i tuted by one or two alkyl groups. Preferred groups are the lower alkyl carbamoyl groups. "Hydroxya I ky I " means an alkyl group subst i tuted by a hydroxy group. Hydroxy lower alkyl groups are preferred and include hyd roxyme t hy I , 2-hydroxyβ t hy I , 2-hyd r oxyp ropy I , and 3-hydr oxypr opy I . "Alkoxy" means an alkyl oxy group in which "alkyl" is as previously descr ibed. Lower alkoxy groups are preferred and ncludβ methoxy, βthoxy, n-propoxy, i-propoxy, sβc-propoxy, n-butoxy among others. "Alkoxyalkyl " means an alkyl group as prev iously descr ibed subst i tuted by an alkoxy group as previously descr ibed. "Al ky I eneami no" means -RNH where -R i s alKylβnβ of I to about β carbon atoms. The preferred groups are the lower a I k I eneami no groups which mean amino groups subst i tuted wi th alkylene groups of I to about 4 carbon atoms. The most preferred a I ky I eneami no group is me t hy I eneami no . The preferred halo group is cloro. Preferred compounds of this invention include those compounds of formulae I I to V where R, i s cyano. The more preferred compounds are those of formulae I I to V where R is hydrogeni R, is cyano and R β i s lower l o al kyl , whi le the most preferred compounds are those of formulae I I and IV where R, is methyl , that i s: 6 VII Compounds of this invent ion may be prepared by the fol lowing reaction sequences: VIII IX XII XIII where Het is as described above Whβn a 2 or 5-( ιmιdazol-1-yl or 1 ,2,4-tr iazol-1-yl )-5 or 2-pyr ιdιne ca r boxa I dehydβ (VI M ) i s treated wi th a l i ium der ivat ive of me t hoxye t h I d i pheny I p o s p i nβ oxide, the adduct ( IX) i s generated. Upon treatment of thi s adduct wi th sodium hydr ide in THF the vinyl ether (X) i s prepared. Hydrolys i s of the resul tant ether wi th di l ute acid (preferably sul fur ic or hydrochlor ic ) in THF resul ts in the preparat ion of the corresponding ketone (XI ) . React ion of the ketone wi th d tmβ t h I formami dβ d ime t h I ace t a I (DMF-DMA) wi th warming fol lowed by treatment , in DMF or the l i ke, wi th cyanoacβ t am i de in the presence of sodium hydr ide resul ts in the desi red 5-13 or 2-(6 or 5- ( 1 H- i m i azo I - 1 -y I or 1H-1 ,2,4-tr iazol-1-yl )ϊ p r idyl 3-1 ,2-dl hyd r o-6-mβ t hy I -2-oxo- 3-py r i d i nβcarbon i t r i I β XI I I . React ion of the ketone XI wi th e t hoxymβ i ny I - enema I onon i t r i I e fol lowing the procedure of Singh [He t βr ocyc I es , 23, 1479 ( 1985)] al so resul ts in the desi red compounds of XI I I . Conversion of the cyano group into the other R, subst i tuents groups may be accompl i shed by techniques known in the art . Treatment of the 1 - ( H) -py r i done compound wi th a sui table alkylat ing agent resul ts in the compounds of the present invent ion wherein R is other than hydrogen. When R is hydrogen the start ing ketone i s reacted wi th me t hoxyme t hy I d i phen I phosph i nβ oxide in place of methoxyβthyldiphenylphosphinβ oxide. The aldehyde starting materials of VI I I may be prepared try the following sequence. M n°2 VIII where Het is as described above. 6-chloronicotinic acid and 5-chloropicol inιc acid are converted to the methyl esters with diazomethane and condensed with 1H-imidazole or 1H- 1 , 2 , 4-t r i azo I e of formula 1 under standard techniques using sodurn hydride in DM . Reduction of the ester to the alcohol fol lowed by normal oxidation procedures using manganese oxide resul ts in the desired aldehydes of formula VI M . Acid addition salts are a convenient form for use. In practice, use of the salt form inherently amoun s to use of the base form. Acids which can be used to prepare the acid addition salts include preferably those which produce, when combi ed with the free base, pharmaceutical ly acceptable salts, that is, salts whose anions are non-to ic to the animal organism in pharmaceutical doses of the salts, so that the benefici l cardiotonic properties inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutical ly acceptable salts of said -9- basi c compound are preferred, al l acid addi t ion sal ts are useful as sources of the free base form even i f the part icular sal t per se is desi red only as an intermediate product as, for example, when the sal t is formed only for purposes of pur i f icat ion and ident i f ica ion, or when i t is used as an intermediate in prepar ing a pharmaceu ical ly acceptable sal t by ion exchange procedures. Examples of pharmaceut ical ly acceptable sal ts wi thin the scope of the invent ion are those der ived from the fol lowing acids: mineral acids such as hydrochloric acid, sul fur i c acid, phosphor ic acid and βul famic acid) and organic acids such as acet ic acid, ci tr ic acid, lactic acid, tar tar ic acid, alonic acid, me t hanesu I fon i c acid, e t hane s u I f on i c acid, benzenesu I fon i c acid, p- to I uenesu I f on i c acid, eye I ohexy I su I f ami c acid, quinic acid, and the l ike. The. corresponding acid addi t ion sal ts comp i sβ t e . fol lowing: hydroch I or i de , sul fate, phosphate, sul famate, acetate, ci trate, iactate, tartrate, malonate, me t hanesu I f ona t e , β t hanesu I f ona t β , benzenesu I f ona t β , p- t o I uenesu I f ona t e , eye I ohexy I su I f ama t e and quinate, respect ively. The acid addi t ion sal ts of the compounds of thi s i nvent ion can be prepared ei ther by di ssolving the free base in an aqueous or aqueous alcohol sol ut ion or other sui table solvent ( s ) contai ni ng the appropr iate acid and i solat ing the sal t by evaporat ing the solut ion, or by react ing the free base and acid in an organic solvent , in which case the sal t separates di rect ly or can be obtained by concentrat ion of the sol ut ion. The compounds of formula I possess pos i t ive inotropic act ivi ty and are useful as cardiotonic agents i n the treatment of humans and other mammal s for card i ac di sorders i.nαluding congest ive heart fai lure. The effec i veness of t'he compounds of this invent ion as inotropic agents may be determined by the fol lowing pha rmaco I og i c tests which evaluate the change in cardiac contracti le force upon exposure to a dose of said compounds. The anesthet ized dog procedure is a standard test procedure; the inotropic resul ts of this procedure general ly correlate wi th the inotropic activi ty found in human patients. -11- Gano I i on i c-Be t a Blocked Anesthet ized DOQ Procedure Adul t mongrel dogs of ei ther sex weighing 10 to 16 kg are fasted overnight, anesthet ized wi th pen toba r b i ta I sodium 35 mg/kg, i .v. intubated, respi red wi th room ai r using a Harvard respi rator, and instrumented surgical ly to moni tor myocardial contract i le force, heart rate, arter ial pressure, aort ic f low and EKG l imb lead I I . The aforesaid measurements are recorded cont inuously on a str ip chart recorder . Myocardial contracti le force is moni tored by a Wa I ton-Brod i e strain gauge sutured to the left ventr icular myocardium paral lel to the left anter ior descending coronary artery. Arter ial pressure is measured using a f luid-f i l led catheter attached to a pressure transducer introduced via the r ight femoral artery and posi t ioned in the thoracic aorta. Mean arter ial pressure i s determined by electronical ly clamping the pulsat i le pressure signal . Aort ic f low i s moni tored using a p r eca I i br a t ed , noncamu I at I ng elec romagnetic f low probe posi t ioned around the thoracic aorta. Heart rate is moni tored using a ca r d i ot achome t e r tr iggered by the ORS complex of the l imb lead I I EKG. The r ight femoral vein is cannulated for intravenous infusion of drugs. Body temperature i s o mai ntained at 37 C. Fol lowing a 30 min postsurgical stabi l izat ion per iod, control values are recorded. Myocardial depress ion i s induced by gangl ionic and beta receptor blockade. Ini t ial ly, the responsi eness of the autonomic nervous system i s assessed by performi ng a 30 sec b i l ateral carot i d occlusion (BCO) . Ten minutes later , a sal ine solut ion of i sop ro tβ r βno I 0.3 mg/kg, i .v. is administered to assess beta receptor integr i ty. Ten minutes af ter that , a sal i ne -12- solution of mβcamylamine 2 mg/kg. i .v. is infused, fol lowed by a sal ine solut ion of propranolol I mg/kg i .v. plus 0.3 mg/kg/hr . Twenty minutes later , a second BCO i s performed to demonstrate gangl ionic blockade fol lowed by a second injection of sal ine i sopro tβ reno I 0.3 mg/kg, i .v. to demonstrate beta blockade. Ten minutes later, the test compound or vehicle is administered intravenously in ascending doses at 30 min interval s at 1.5 ml/mi n in a total volume of 3.5 ml . On complet ion of the exper iment, both BCO and i sop ro t e reno I chal lenges are repeated to ver i fy gangl ionic and beta blockade. The resul ts of the blocked dog test show that compounds of the present invent ion increase contract i le force and heart rate, and aort ic blood f low In a dose related manner whi le maintaining arter ial pressure. Additional test procedures which have been found to be . an efficient means for ascertaining the inotropic activi ty of the compounds of this invention are descr ibed below. Guinea Pio Atr ia I notropic Screening Concentrat ions Guinea pigs are stunned by a sudden blow to the head* thei r chests are opened and hearts exci sed and placed in Kreb's medium (concentrations, mM: NaCI , 118.39s KCI , 4.70; MgS0 4 , I .18; KH^P0 4 , 1.18; NaHCOg , 25.00ι glucose, 11.66 and CaCI., 1.25 gassed wi th a mixture of 95% 0 Λ . Left atr ia are 2 o 2 removed and inserted into warmed 33 C) double jacketed t issue chambers containing oxygenated Kreb's medium (as above) . The upper end of each t issue is attached to a Statham Universal Transducing Cel l via a Statham Microscale Accessory. Rest ing tension on each t issue is set at Ig and adjusted per iodical ly. Mass ive field st imulat ion i s ac ieved via a pai r of plat iunum or si lver electrodes placed on opposi te sides of the tissue. Electrodes are made from 2-gaugβ si lver wi re wound into a t ight coi l approximately 12-14 mm i n diameter . Electrodes are connected to a Grass st imulator via a Grass -13- constant cur rent un i t . Ti ssues are dr i ven at 90 pul ses per minute wi th 5 msec durat ion at current leve l s 20% greater than threshold for cont i nuous beat . Cumulat ive concentra ions of test drugs are added to the t i ssue bath at interval s suf f icient to al low developed tension to peak at a new level . The increase in developed tension in each t i ssue for each compound concentrat ion i s measured, and the resul ts are averaged and used to construct cumulat ive concen r a t i on- r e spon se curves . Slopes for these regressions calculated via the method of Finney ( 1971) are compared using Student 's t-test The fol lowing jji vi tro method is another means for measur ing the inotropic potency of the present compounds. Thi s method is a modi f icat ion of the enzyme inhibi t ion method reported by Thompson and Appleman ( 1970) and Thompson a t a I (1974) , and is bel ieved to correlate to j_Q. vivo inotropic act ivi ty in humans. Inhibi t ion Of Peak I I I cAMP Phosphod i e s t e r as e Act ivi ty The test compounds are included in media compr i sing -*. 3 r ad i oac t i vβ I y labeled substrate ( H-cycl ic nucleot ide) such as adβnosine 3 ' : 5 ' - onophospha t β (cycl ic AMP) and guanos i ne-3 ' : 5 ' -nuc I eo t i dease i solated from a dog heart . The inhibi t ion of the enzyme hydrolysis of the 5 ' -nuc I eo t i dβ product of the cNUC-PDEase to the corresponding nuclβos ide i s measured by separat i ng the charged, unhydrol yzed -14- substrate from the uncharged hydrolysis product . Separation may be achieved ei ther chroma t og r aph i ca I I from the uncharged nucleoside product of the assay wi th ionβxchange res in so that i t is not quant ated wi th the l i quid scinti l lat ion counter . Anesthetized Doa Procedure Male mongrel dogs are anesthet ized wi th pe toba r b i t a I C35 mg/kg i .v.) and in tuba ted. Femoral artery and veins are cannulated for measurement of blood pressure and inject ion of compounds, respect ively. A catheter connected to a Statham transαucer i s inserted into the left ventr icle via the r ight carotid artery for measurement of left ventricular pressure, left ventr icular end diastol ic pressure and dP/dt . Lead M ECG and heart rate are also moni tored. AM parameters are measured on a Bβckman Dynagraph. Two addi tional test procedures which have been found to be an eff icient means for ascertaining the inotropic activi ty of the compounds of thi s invent ion are descr ibed be I ow. -15- Conscious Instrumented Dog Female mongrel dogs ( 18.0 - 18.5 kg) are anesthet ized wi th sodium pen toba r b i a I (35 mg/kg i .v. , supplemented as necessary dur ing surgery) intubated and connected to a Harvard respi rator . The left side of the chest is opened at the f ifth intercostal space, and a Konigsberg transducer inserted into the left ventr icle through a puncture at the apex and secured. A f luid-f i l led polyethylene catheter is inserted into the left a r ium through a puncture wound and secured for measurement of left atr ial pressure. A second f luid-f i l led catheter is inserted i nto the aor ta for measurement of blood pressure and heart rate and secure, to the vessel wal l . The two catheters and the Kon i gsberg transducer cabl e are passed out of the chest through the seventh i ntercostal space and advanced subcutaneous !y to the back of the neck and passed through the sk in . The f luid-f i l led catheters are f i l l ed wi th hepar in i zed 50% dextrose solut ion, and the chest i s closed and evacuated. The dogs are treated dai ly pos -ope r a t i ve I y wi th 600,000 uni ts of pen i c i I l i n-p r oca i nβ i .m. for ten days and wi th ch I o r amphen i co i , 500 mg/kg i .m. , every other day for 10 days and al lowed at l east 7 days recovery before use. -16- Each dog i s trained and accl imated to i ts env i ronment and the presence of personnel dur ing the experiment. The dogs are fasted overnight before ei ther intravenous or oral admini str ion of the compound. On a test day, the dog is placed in a sl ing and connected to a recorder (Gould Instruments or Grass Instruments) for measurement of left ventricular pressure, left ventr icular and diastol ic pressure, left ventr icular dP/dt , blood pressure, heart max rate (from the blood pressure signal ) , and the lead M electrocardiogram. The compound is administered both intravenously and oral ly ( l iquid and soft gelat i capsule forms) in different exper iments and blood samples were taken for determinat ion of blood levels of the compound. The compounds of t is invention can be norm l ly administered oral ly or parenteral ly, in the treatment of cardiac disorders such as heart fai lure in humans or other mamma I s . The compounds of this invent ion, preferably in the form of a sal t , may be formulated for admini stra ion in any convenient way, and the invent ion i ncludes wi thi n i ts scope pharmaceut ical compos i t ions containing at least one compound according to the invent ion adapted for use i n human or veterinary medici ne. Such compos i t ions may be formulated in a convent ional manner us ing one or more pharmaceut ical ly acceptable carr iers or excipients. Sui table carr iers include di luents or fi l lers, steri le aqueous media and var i us non-toxic organic solvents. The composi t ions may be -17- formulated in the form of tablets, capsules, lozenges, troches, hard candies, powders, aqueous suspens ions, or solut ions, injectable solut ions, el ixi rs, syrups and the l ike and may contain one or more agents selected from the group including sweetening agents, f lavoring agents, color ing agents and preserving agents, in order to provide a pharmaceut i cal ly acceptable preparat ion. The part icular carr ier and the rat io of inotropi c act ive compound to carr ier are determined by the solubi l i ty and chemical propert ies of the compounds, the part i cular mode of administrat ion and standard pharmaceut ical pract ice. For example, βxcipients such as lactose, sodium ci trate, calcium carbonate and i calcium phosphate and var ious d i s i n eg r a tan t s such as starch, alginic acid- and certain complex si l icates, together wi th lubr icat ing agents such as magnesi um stearate, sodium lauryl sulphate and talc, can be used in producing tablets. For a capsule form, lactose and high molecular weight polyethylene glycol s are among the preferred pharmaceu ical ly acceptable carr iers. Where aqueous suspensions for oral use are formulated, the carr ier can be emul si fyi ng or suspending agents. Di luents such as ethanoi , propylene glycol , glycer in and chloroform and thei r combinat ions can be employed as wel l as other mater ials. For parenteral admi n i s rat ion, sol ut ions or suspens ions of these compounds in sesame or peanut oi l or aqueous -18- proplyene gtycol solut ions, as wel l as ster i le aqueous solutions of the soluble pharmaceut ical l acceptable sal ts descr ibed herein can be employed. Solut ions of the sal ts of these compounds are especial ly sui ted for intramuscular and subcutaneous injection purposes . The aqueous solut ions, including those of the sal ts di ssolved in pure dist i l led *.te-r„ are al so useful for intravenous injection purposes, provided that thei r pH is properly adjusted, sui tably buffered, made isotonic wi th suff icient sal ine or glucose and ster i l ized by heat ing or by microf i l trat ion. The dosage regimen in carrying out the methods of this invent ion is that which insures maximum therapeutic response unti l improvement i s obtained and thereafter the minimum effect ive level w ich gives rel ief . Thus, i n general , the dosages are those that are t he r apβu t i ca I I y effective in increasing the contract i le force of the heart or in t e treatment of cardiac fai lure. In general , the oral dose may be between about 0.01 mg/kg and about 50 mg/kg (preferably in the range of 0.1 to 10 mg/kg) , and the i .v. dose about 0.005 to about 30 mg/kg (preferably in the range of 0.01 to 3 mg/kg ) , bear i ng in mind, of course, that in selecting the appropr iate dosage in any speci f ic case, consideration must be given to the pat ient 's weight , general heal th, age and other factors which may inf luence response to the drug. The drug may be administered as frequently as i s necessary to achieve and sustain the desi red therapeut ic response. Some pat ients may respond quick ly to a relat ively large or smal l dose and requi re l i ttle or no maintenance dosage. On the other hand, other pat ients may requi re sustained dos ing from about one to about four t imes a day depending on the physiologi cal needs of the part icular pat i ent . Usual ly the d-r ug^ may be admi n i stered ora l l y I to 4 t imes per day. I t i s ant icipated that many pat ients wi l l requi re no mo e than about one to about two doses dai ly. I t i s al so ant icipated that the present i nvent ion would be useful as an i njectablβ dosage form whi ch may be admi ni stered in an emergency to a pat ient suffer ing from acute cardiac fai lure. Such treatment may be fol lowed by intravenous infusion of the act i ve compound and the amount of compound infused i nto such a pat ient should be effect ive to achieve and maintain the desi red therapeut ic response. Compounds of thi s invent ion rrι α y i « μ , .s ar e by the fol lowi ng react ion sequences. EXAMPLE 1 2-lmidazolyl-5-pyridinβcarboxaldβhydβ Step I . 6-Ch I oron i cot i n i c acid, methyl ester An ethereal solution of CH N. (0.1 mole) i s added to a suspension of 6-chloronicot inic acid (15 g ) in CH Cl. unti l bubbl ing ceases. The react ion mixture is st i rred overnight, evaporated and dried i yacuo affording the desired product o o as an off-white sol id M.P. = 83 -85 C. Step 2. 6-( 1 -H- Imi dazo I - 1 -v I )-n i cot i n i c acid, methyl - ester A solution of the methyl ester obtained in Step 1. above ( 16.29 g) in DMF is added dropwise to a DMF suspension of sodium imidazole (prepared from NaH (4.19 g) and imidazolβ ( 6.49g ) ] at RT. The react ion mixture is heated to 120 C for nineteen hours . The cooled react ion mixture is partit ioned between water and chloroform, the organic layer separated, washed wi th water , dr ied over Na„SO. , f i l tered, 2 4 evaporated, and residual DMF removed under high vacuum yielding the des i red product as a tan sol id which is recrys ta I I i zed r om me thano I . M.P.= 200°-202°C. -21- Step 3. 2-(1H-lmιdazol-1-yl )-5-hvdroxymethyl pyr idine NaBH. (37.82 g) i s added port ionwi se to a suspens ion of the imidazolyl ester of Step 2. above ( 9.98 g ) in methanol at about 0 C. The react ion mixture is heated to ref lux for 7 1/2 hours , al lowed to cool and stand 15 hours . Water (75 ml ) is added, and the quenched reaction mixture evaporated, affording a sol id residue which i s suspended i n water , extracted wi th chloroform, f i l tered, dr ied over Na SO , evaporated, and r βc r ys t a I I i zed (CHCI ) , affording the desi red product as a whi te sol id. M.P. = 124-126.5°C. Step 4. 2-( 1H-lmιdazol-1-yl )-5-pyr ldi necarboxaldehyde MnO. ( 18.17 g) i s added to a solut ion of the hydroxy methyl compound of Step 3. above (6.1 g) in CHC 1. , and the 3 resul t ing react ion mixture heated to ref lux for 22 hours, al lowed to cool , fi l tered, and the organic layer evaporated affording the desi red product as a whi te sol id. M.P. = 136-137.5°C. EXAMPLE 2 When the procedure of Example I i s fol lowed and the 6-c I o r on i co i n i c acid i s replaced wi th 5-c h I o r op i co I i n ι c acid i n Step 1 , then the product obtai ned i s 5- ( 1H-ιmιdazol-1-yl )-2 pyr idinecarboxaldehyde. -22- EXAMPLE 3 When the procedures of Examples I and 2 are fol lowed and 1H-imidazole is replaced wi th 1H-1 ,2,4-tr iazole in Step 2. , then the products obtained are 2-( 1H- I , 2 , 4- tr i azo I - 1 - y I ) -5-py r i d i nβ carboxa I dehyde and 5-( 1 H- I , 2 , 4-1 r i azo I - 1 - I )-2-py r i d ϊ nβ ca r boxa I dehyde . EXAMPLE 4 5-t3-t6-C1H-lmidazol-1-yl )} pyr idyl l- 1 ,2-dϊhydro-6-methyl-2-oxo-3-pyr idinβcarboni tr i le Step 1. 2-Diphenylphosphinoyl-2-methoxy-1-[3- C6-( 1H- Imi dazo I - 1 -v I ) } pyridyl ] propan-1-ol Methoxyethyldiphenylphosphine oxide (0.70g, 2.68 mmo I ) in dry THF (3ml ) is sti rred wi th l i thum di-l sopropyl amide (LDA) [from d ϊ - i sop ropy I ami nβ C0.61g) and n-BuLi (2.2ml ; 2.5M solution in hexane] in THF ( 12ml ) at 0 C for 30 min. The mixture is cooled to -78 C and 2-( imidazol-1-yl )-5- pyr i d i neca rboxa I dehyde (0.42g, 2.44 mmo I ) in dry THF ( 7m I ) is added dropwi se. The solution is al lowed to warm to room temperature over 40 min. and saturated aqueous ammonium chloride solution C30ml ) and ether (40ml ) are added. The aqueous layer is extracted wi th ether (3x40ml ) , and the combined organic layers dr ied (Na SO ) and evaporated to gi ve a yel low oi l . Col umn ch r o a t og r ap y (E tOAc-met hano I - t r i e t hy I ami nβ ( 19: 1 : 1 ) 1 gi ves 0.36g of the al cohol . Step 2. 1-r3-[6-( 1H-lmidazol-1-yl ) }Pyr idyl 3-2- methoxy-prop-1-ene A mixture of the alcohol obtained in Step 1. ( 2.30g, 5.31 mmo I ) in 100 ml of THF i s st i rred wi th sodi um hydr ide ( 1.28gι 50% di spersion in oi l ) for I 1 /2 hour , then poured into br ine (100ml ) and extracted wi th ether ( 4x100ml ) . The combined organi c extracts are dr ied (Na 2 S0 4 ) and evaporated to g i vjs the vinyl ether which i s used in the next step wi thout further pur i f ica ion. Step 3. 1-[3-{6-( 1H-lmidazol-1-yl ) 1pyr i dyl 3-2- propanone A solut ion of the vinyl ether (0.90g, 4.18 mmo I ) obtained in Step 2. above i n 80 ml of THF i s treated wi th IN H SO ( 19ml ) and st i rred at 23°C for I hour . The mixture i s poured into H O ( 100ml ) which i s st i rred br ief ly, made basic wi th 30% aqueous NaOH, and extracted with ether (5x50 ml ) . The combined org » anic lay / ers are dried CNa2 Λ SO4.) and evaporated to produce an oi l which i s ch roma tog r aphed [us in ethyl ace ta t β-me t hano I - t r i e thy I ami ne (38: 1 : 1)as the eluentl to give pure propanone as a crystal l ine sol id. M.P. = 74-77°C. Step 4. 4-(Dιmethylamino)-3-C3-f6-( 1H-imidazol-1-yl )} pyridyl 1-3-buten-2-one A mixture of the propanone (0.50g, 2.48mmol ) obtained in Step 3. in 5ml of d ime t hy I formami de-d imβ t hy I ace ta I (DMF-DMA) is st i r red and warmed at 80 C for 12 hours. The excess DMF-DMA is evaporated under reduced pressure to generate an oi l whi ch i s ch r oma t og r aphed (using ethyl ace tat e-me thano I (8:2) as the el uent) to give the des i red product as a sol id. M.P. = 117°-122°C. Step 5. 5-C3-(6-C1H-lmidazol-1-yl ) } oyr idvU- 1.2-d i hvd ro-6-me thyl-2-oxo-3-oyr idinecarboni tr i le A solution of the above butβn-2-one (0.53g, 2.07 mmo I ) obtained in Step 4. in 5ml of DMF is added dropwi se to Na (0.186g; 50% di spersion in oi l ) and cyanoacet amide (o. l9g, o 2.28 mmo I ) in 5 ml of DMF. The mixture is sti rred at 23 C -25- for 4 hours , quenched wi th saturated aqueous ammon ium chlor ide, and the resul t ing precip i tate f i l tered to give the desi red product as a sol id. M.P = 32β°-329°C EXAMPLE 5 When the procedure of Example 4 i s fol lowed and the 2- ( 1H- i m i dazo I - 1 -y I ) -5-py r i d i eca r boxa I dβhydβ of Step 1. i s replaced wi th the aldehydes of Examples 2 and 3 then the corresponding products of Table I below are prepared. Tab I e I 5-[3-(6-( 1H-1 ,2,4-tr iazol-1-yl )) pyr idyl l-1 ,2 dι hydro-6-methy l-2-oxo-3-pyr idi nβcarbon i tr i I β . 5-(2-C5(1H-ιmιdazol-1-yl ) ) pyr idyl 1-1 , 2- dι hydro-6-methyl-2-oxo-3-pyr id ι necarbon ι t r i I β . 5-C2-t5-( 1H-1 ,2,4-tr ιazol-1-yl ) ) r i yl ) - 1 , 2-d i hydro-6-mβ thyl-2-oxo-3-pyr idi nβcarboni tr i I β .

Claims: -26- CLAIMS : A compound of the formula whe rβ Het is imi dazo I -1-y I or 1 , 2 , 4- t r i azo I - 1 -y I ι x i s -CH=N-or -N=CH-; and R. are H or al yl and R is H, alkyl , a I oxya I ky I , hydroxyalkyl , cyano , car bamoy I , a I y f car bamoy I , fo rmy I , al kyl enearn i no or ami no ; or a pharmaceut ic l ly acceptable sal t thereof . A compound according to claim 1 where R, i s cyano A compound according to claim 2 where R hydrogen A compound according to claim 3 where R i s I owe r a I ky I A compound according to claim 4 where R e i s methyl 6. A compound according to claim 5 which i s 5- 13- ( 6- ( 1H-imidazol-1-yl )) pyr idyl 3-1 ,2-di hydro-6-mβ thyl-2-oxo-3- py r i d i nβcarbon i t r i I β . 7. A compound according to claim 5 which i s 5-C3- (β-(1H-1 ,2,4-tr iazol-1-yl ) ) pyr idyl ]-1 ,2-di hyd r o-β-mβ t hy I -2 oxo-3-pyr idinecarboni tr i Iβ. 8. A compound according to claim 5 whi ch i s 5- [2-(5-( 1H-imidazol-1-yl )) pyr idyl 1-1 ,2-di hyd r o-6-me t hy I -2-oxo-3-pyr idinβcarboni tr i le. 9. A compound according to claim 5 whi ch i s 5- [2-f 5-( 1H-1 ,2 ,4- t r ιazol-1 -y I ) ) p r i dy I 1 - 1 , 2-d i d r o-6- mβthyl-2-oxo-3-pyr idinecarboni tr i Iβ. 10. A method for increasing cardiotonic contracti ity in a pat ient requi ring such treatment which compr ises administer ing to such pat ient an effect ive amoun of a compound according to claim 1. 11. A pharmaceutical composi t ion for increasing cardiotonic contracti l i ty in a patient requi r ing such treatment comprising a compound according to claim 1.

Inventors: CAMPBELL HENRY F, FAITH WILLIAM C, KUHLA DONALD E, CAMPBELL, HENRY, F., FAITH, WILLIAM, C., KUHLA, DONALD, E.
Applicants: RORER INT OVERSEAS, RORER INTERNATIONAL (OVERSEAS) INC.
Application year: 1987
Main classification: A61K31
IPC codes: A61K31, A61P9, C07D401, C07D521