PYRIDOPYRIMIDINONES

Abstract: The invention relates to compounds of the Formula IV which are useful as antiarrhythmic agents.

Description: PYRIDOPYRIMIDINONES BACKGROUND. OF THE INVENTION (a). Field of the invention This invention relates to novel pyridopyrimidinones useful as antiarrhythmic agents. In particular, the invention relates to novel pyridopyrimidinones of the Formulas which are useful in the treatment of arrhythmic disorders. Arrhythmias are disorders relating to impulse generation in the heart. The disorders include premature contractions (extrasystoles) originating in abnormal or ectopic-foci in atria or ventricles, paroxysmal supraventricular tachycardia, atria flutter, atrial fibrillation, and ventricular tachycardia and fibrillation. For.a discussion on these disorders see for example the Pharmacological Basis of Therapeutics, Goodman and Gilman, the MacMillan Cho., pgs. 709-711 (1970). A number of compounds have been developed to alter cardiovascular function related to heart rate and rhythm. The cardiac glycosides, including digitalis, have as their main pharmacodynamic property the ability to increase the force of myocardial contraction. The salutary effects of the drug in congestive heart failure -- increased cardiac output, decreased heart size, venous pressure and blood volume; diuresis and relief of edema -- are all explained on the basis of increased contractile force, a positive inotropic action. Quinidine is useful in the therapy of atrial fibrillation but exhibits several toxic reactions, such as cinchonism; The cardiac actions of procainamide are essentially identical to those for quinidine, and like quinidine, procainamide exhibits toxic side effects. Lidocaine, a widely used local anesthetic administered jinitavenously may be used in the treatment of ectopic 1ventricular rhythms, but is not recommended for the treatment of supraventricular arrhythmias. Propranolol has found use in the treatment of supraventricular tachycardias and ventricular arrhythmias but because propranolol antagonizes adrenergic effects on contractility and because serious arrthymias are commonly encountered in the presence of overt or incipient heart failure, the use of the drug for its antiarrhythmic actions demands great care. Disopyramide is similar to procainamide and quinidine (referred to as a Type 1 antiarrhythmics). At therapeutic plasma levels disopyramide shortens the sinus node recovery time, lengthens the effective refractory period of the atrium and has a minimal effect on the effective refractory period of the AV mode;. However, because of the anticholinergic effects of some of the Type 1 | antiQrrhythmics, they should not be used in patients with glaucoma, myasthenia gravis or problems of urinary retention. (b) Prior Art As previously described, a number of compounds are useful in the treatment of arrhythmias. The pyridopyrimidinones of the instant invention are novel and represent a new class of compounds useful to treat arrhythmias with reduced anticholinergic activity. SUMMARY OF THE INVENTION It is an object of this invention to develop new chemical compounds with reduced anticholinergic activity that are useful in the treatment of arrhythmic conditions. In accordance with this objective, it has been discovered that compounds of formula: EMI4.1 wherein R1 is: a) hydrogen; b) alkyl of from 1 to 6 carbon atoms, inclusive; c) phenyl; wherein Y is: a) hydrogen; or b) EMI4.2 wherein each X is a substituent taken independently, selected from the group consisting of:: a) hydrogen; b) halogen; c) alkyl of from 1 to 6 carbon atoms, inclusive; ; d) alkoxy of from 1 to 6 carbon atoms, inclusive; or e) phenyl; wherein Z is: a) hydrogen; b) -(CH2)n-NR2R3, wherein n is 1 to 6; wherein R2 and R3 are: a) alkyl of from 1 to 6 carbon atoms, inclusive, R2 and R3 each being the same or different; or wherein R2 and R3 are taken together to form a cyclic structure either saturated or unsaturated of from 4 to 6 carbon atoms, inclusive; wherein R4 is: a) a) hydrogen; or ( b) alkyl 1 to 6 carbon atoms, inclusive; and the pharmacologically acceptable salts are useful for their antiarrhythmic activity and exhibit reduced anticholinergic activity. Examples of alkyl of from 1 to 6, inclusive, are methyl, ethyl, propyl, butyl, pentyl, heyl and isomeric forms thereof. Examples of halogen are chloro and bromo. Examples of alkoxy of from 1 to 6 carbon atoms, inclusive are methoxy, ethoxy, propoxy, butoxy, pentexy, hexoxy and isomeric forms thereof. Examples of saturated nitrogen-containing cyclic structures of 5 to 7 atoms, inclusive, are 1-azacyclo pentyl, 1-azacyclohexyl and 1-azacycloheptyl. Examples of unsaturated nitrogen-containing cyclic structures ot 5 to 7 atoms, inclusive, are l-pyrrolinyl, l-pvrrolyl, 1-dihydropyridinyl, 1-tetrahydropyridinyl, 1-azacycloheptenyl, 1-azacycloheptadienyl, 1-azepinyl. Antiarrhythmic activity was confirmed using ventricular arrhythmia induced in unanesthetized dogs. Ventricular arrhythmia is induced by a two-stage ligation of the anterior decending branch of the left coronary. artery in each of two or more dogs. A test compound is rated active if it produces at least a 25% reduction in ectopic beats for a period of at least 10 minutes in half or more of the dogs tested. An active compound may act by I supprfissing the ectopic pacemaker, thus allowing normal sinus rhythm to return. This arrhythmia is considered similar in nature to the arrhythmia resulting from myocardial infarction in man Quinidine and procainamide are active in this test and are effective in man. By virtue of the antiarrhytlunic activity, the compounds of Formula V are useful in treating arrhythmias in mammals. A physician or veterinarian of ordinary skill could readily determine a subject who exhibits arrhythmias. Regardless of the route of administration selected, the compounds of the present invention are formulated into |pharmaceutically acceptable dosage forms by conventional methods known to those familiar with the pharmaceutical art. The compounds can be administered in such oral unit dosage forms as tablets, capsules, pills, powders, or granules. They also may be administered intraparitoneally, subcutaneously, or intramuscularly, using forms known to those familiar with the pharmaceutical art. In general, the preferred form of administration is oral. An effective but non-toxic quantity of the compound is employed in treatment. The dosage regimen for preventing or treating arrhythmia by the compounds of this invention $'is selected in accordance with Åa variety of factors including the type, age, weight, sex, and medical condition of the patient, the severity of the arrhythmia, the route of administration and the particular compound employed. An ordinarily skilled physician or veterinarian will readily determine and prescribe the effective amount |of the antiarrhythmic agent to prevent or arrest the progress of the condition. In so proceeding, the physician or veterinarian could employ relatively low dosages at first, subsequently increasing the dose until a maximum response is obtained. Initial dosage-s of the compounds of the invention are ordinarily in the area of l.O mg/kg up to at least 10.0 mg/kg orally. The compounds of this invention can nlso be administered as pharmacologically acceptable acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, tartrate and the like. Additionally, the compounds of this invention may be adm-.nisXered in a suitable hydrated form The compounds of this invention are prepared according to the general scheme on Chart A from the available racemic butanamides, I. Reduction of the pyridine ring of I, in which a new chiral center is formed, gives a mixture of four diastereomers, II. This may be accomplished by catalytic hydrogenation-using catalysts such as Raney nickel, platinum, palladium or the like, or reaction with 'an alkali metal, such as sodium or lithium, -n ammonia. The mixture of four compounds can be separated, for example by crystall@zation, into two pa@@s @@ @acema@es before further reactions are performed. In general, as ican be expected for racemates, each racemic pair exhibits distinct and reproducible physical properties such as melting point and NMR spectra, and each racemate can be distinguished from the other by these and other properties. The intermediate compounds II are cycled to corresponding diazabicyclic compounds III, for example by reaction with a dialkyl ketal or acetate of an amide, with an orthoester, or with other reactive formyl equivalents. Examples of amides which can be used as their ketals or acetals include dimethylformamide, dimethylacetamide, and dimethylbenzamide. Examples of orthoesters include triethylorthoformate, triethylorthoacetate, and triethylorthobenzoate. Examples of other reactive formyl equivalents include bis(dimethylamino)methoxymethane and fris(dimethylamrno)methane. These bicyclic compounds can in turn be converted to compounds V by seductive procedures, for example catalytic hydrogenation, using Raney nickel, platinum, palladium or the like, or reaction with an active metal hydride such as lithium aluminum hydride, sodium borohydride, or one of the available derivative variations of'these reagents. Compounds of Formula V can for example be prepared via the method in Example 24. The following examples further illustrate details for the preparation and testing of the compounds and salts of the invention. The invention, which is fully set forth in the foregoing disclosure, is not to be construed as being j limited either in spirit or scope by these examples. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can also be used to prepare the compounds of the invention. All temperatures are in degrees celsius unless otherwise noted. DESCRIPTION OF THE PREFERRED EMBODIMENTS Example 1 Preparation of 2-phenyl-2-(2-piperidinyl)- 4-[N,N-bis(1-methylethyl)amino]butanamide, Racemate A(II). A mixture of 105.3 g (0.31 mole) of racemic 2-phenyl-2 (2-pyridyl)-4-[N,N-bis(1-methylethyl)amino]butanamide and 27 ml (ca. 0.32. mole) of concentrated aqueous hydrochloric acid in 2.5 liters ot ethanoi was hydrogenated (50 psi) over platinum oxide catalyst After filtration to remove the catalyst, the reaction mixture was reduced to a syrupy residue, dissolved in-an ice/water mixture, and neutralized with a slight excess of 25% sodium hydroxide. The product mixture was extracted into diethyl ether, which was dried over magnesium sulfate, filtered, and concentrated to dryness, The crude product was crystallized twice from Skellysolve B containing a small amount of diethyl ether, to yield 26.0 g of the title compound as a white solid, m.p. 107-108 . Structure assignment was confirmed by proton and carbon 13 NMR spectra and by elemental analysis. H-NMR(CDCl3)#ppm 0.83, 0.92, 7.33 Example 2 Preparation of a 2-p1'enyl-2-(2-piperidinyl) 4-[N,N-bis(1-methylethyl)amino]butanamide, Racemate B(II) The final filtrate from Example 1 was concentrated under a stream of nitrogen to an oil which slowly solidified. The crude material was chromatrographed several times on silica gel to yield a total of 17 g of the title compound as a white..solid, m.p. 81-82 . Structure assignment was confirmed by proton and carbon 13 NMR spectra and by elemental analysis. H-NMR(CDC13) dppm 0.96, 1.05, 7.30. Example 3 An alternative preparation of 2-phenyl-2-(2piperidinyl)-4-[N,N-bis(1-methylethyl)amino]butanamide. The compounds of Examples 1 and 2 were prepared by hydrogenation in the same manner as in Example 1, except that about 1.3 1 of acetic acid was used as solvent and no hydrochloric acid was added. Example 4 Preparation of 5-phenyl-5-[2-[N,N-bis (1-methylethyl)amino]ethyl]-1,3-diazabicyclo[4.4.0]oct-2-en-4-one, Racemate' A(III). IA A solution of 16.35 g (47 mmole) of Racemate A(II) (of Example 1) and 8.9 g (60 mole) of dimethylformamide dimethyl acetal in 100 ml of dimethyiformamide was stirred overnight under nitrogen at room temperature. Water was added, and the resultant precipitate was collected, washed thoroughly with water, and dried, yielding 12.9 g of the title compound as a white solid. Structure assignment was supported by NMR and by elemental analysis. C H - N Characteristic Peaks Calc'd 74.33 9.36 11.82 NMR(CDCl3) Ippm 0.77, 0.82, 0.85, 0.90, 7.18, 7.25, Fd. 74.27 9.51 11.91 IR(CHCl3) 2980, 1685, 1580 cm 6V(MeOH) Xmax 274-5 mm. Example 5 Preparation of 5-phenyl-5-[2-[N,N-bis(1-methyl- |ethyl)amino]ethyl]-1,3-diazabicyclo[4.4.0]octan-4-one, Racemate A(V). A solution of 14.0 g (39.4 mmole) of Racemate A(III), prepared by the method of Example n, in 260 ml of ethanol was hydrogenated (5 psi) over 5% palladium on carbon. After the catalyst was removed by filtration, the solvent was removed from the filtrate to give a white solid. |Recrystallizaton from ethyl acetate afforded 10.0 g of the title compound, m.p. 204-206 . Structure assignment was confirmed by proton and carbon 13 and and infrared spectra and by elemental analysis. C H N Calc'd 73.91 9.87 11.75 NMR(CDCl3)#ppm 1.03, 1.06, 1.12, 1.15, 7.15 Fd 73.90 9.71 11.83 IR(CHC13) 3410, 2985,.16.80 cm-1 Example 6 Preparation of 5-phenyl-5-[2-[N,N-bis(1-methyl ethyl)amino]ethyl]-1,3-diazabicyclo[4.4.0]oct-2-en-4-one, Racemate B(III). The title compound was prepared by the method of Example 4 using 1.7 g (4.9 mmole) of Racemate B(II) (of Example 2) and 1.0 g of dimethylformamide diethyl acetal in 12 ml of dimethylformamide. After one day the solution was concentrated to dryness in vacuo. The.residue was recrystallized from diethyl ether to give the title compound as a white solid. Structure assignment was confirmed by proton NMR, ultraviolet, and infrared spectra and by elemental analysis, M.P. 155 -158 C. C H N NMR(CDCl3 @ppm 0.80, 0.82, 0.89, 0.91, 7.29 tCalc'd. 74.33 9.36 11.82 pv(MeoH) Xmax 273-274 mm Fd. 74.22 9.53 11.84 IR(CHC13) 280, 1680, 1585 Example 7 Preparation of 5-phenyl-5-[2-[N,N-bis(1-methyl- ethyl)maino]ethyl]-1,3-diazabicyclo[4.4.0]octan-4-one, Racemate B(V). The title compound was prepared by the method of Example 5 using 200 mg (0.56 mmole) of Racemate B(III) (of Example 6). The reaction mixture was concentrated to dryness and the residue was triturated with diethyl ether. - The structure of the product, -a white solid (0.18 g), was confirmed by proton NMR, infrared, and ultraviolet spectra and by elemental analysis, M.P. 164 -166 C. C H N Calc'd 73.91 9.87 11.75 NMR(CDCl3)#ppm 1.00, 1.10, 7.05, 7.55 Fd. - 74.00 9.85 11.65 Example 8 Preparation of 2-methyl-5-phenyl-5-[2-lN,N-bis- (1-methylethylamino]ethyl]-1,3-diazabicyclo[4.4.0]oct-2-en-4 -one, Racemate A(III, R1-methyl). A mixture of 20.0 g (57.0 mmole) of Racemate A(II) (of Example 1) and 22.0 g (165 mmole) of N,N-dimethylacetamide dimethyl acetal was heated at 800 for about 14 hours. After cooling, the reaction mixture was diluted with diethyl ether, filtered, washed with diethyl ether, and air-dried, giving 6.0 g of the title compound, m.p. 191-192 . The product had the expected elemental composition. C H N Calc'd. 74.75 9.55 11.37 NMR (CDCl3) :#ppm 0.77 0.80, 0.87, 0.90, 1.95,m 7.23 Fd 74.49 9.57 11.39 IR (CHCl3) 2970, 1675, 1540 1480 cm 1 v (MeOH) #max 273.274 mm. Example 9 Preparation of 2-methyl-5-phenyl-5- L2-N,N-bis (1-methylethyl)amino] ethyl] -1,3-diazabicyclo [4.4.0] oct-2-en-4-one, Racemate B(III,R1=methyl). The title racemate is prepared by the method of Example 8 using Racemate B (II) (of Example 2). Example 10 Preparation. of 2-methyl-5-phenyl-5- C2-LN,N- bis (1 -methylethyl) aminoj ethyl) -1, 3-diazabicyclo (4.4.0) - octan-4-one, Racemate A(V, R1=methyl). To a solution of 2.8 g (7.6 mmole) of.Racemate A (III, R1=methyl) (of Example 8) in 40.ml of freshly distilled tetrahydrofuran was added, in portions, 0.57 g (15.0 mmole) of lithium aluminium hydride. The.mixture was stirred at ambient temperature for two hours and then cooled in an ice bath. The reaction was quenched by adding 1.2 ml of water, 1.2 ml of 15% aqueous sodium and another 3.0 ml of water, and the resulting precipitate was removed by filtration. The filtrate was concentated to dress, and the residue dried in vacuo at about 500 for 12 to 15 hours, giving 2." g of the the | title compound as a white solid. Structure assignment was confirmed by proton NMR and infrared spectra and by elemental analysis, M.P. 70 -75 C. C H N Calc'd. 74.35 10.04 11.31 NMR (CDCl3) #ppm 0.99, 1.01, 1.08, 1.10, 1.28, 1.35, 7.50 Fd. 74.36 9.95 11.34 IR (CHCl3) 3400, 2985, 1665 Example 11 Preparation of 2-methyl-5-phenyl-5-[2-N,N-bis- | (1-methylethyl)amino]ethyl]-1,3-diazabicyclo[4.4.0]octan-4 one, Racemate B(V, R1=methyl). The title racemate is prepared by the method of Example 10 using Racemate B(III) (of Example 9). Example 12 Preparation of racemic 2-(4-phenylphenyl)-2- (2-pyridyl)-4-[N,N-bis(1-methylethyl)amino]butanenitrile. A mixture of 50.0 g (0.16 mole) of 2-(4-phenylphenyl)-4 [N,N-bis(l-methylethyl)aminolbutanenitrile and 29.7 g of potassium hydroxide (about 0.26 mole as a 35% dispersion in oil) in 1000 ml of toluene was heated at 650. A solution of 32 g (0.20 mole) of 2-bromopyridine in 450 ml of toluene was added slowly. After addition was complete, the mixture was stirred an additional 30 minutes, cooled in an ice bath, and treated with 750 ml of water. The toluene layer was separated and extracted with 10% aqueous hydrochloric acid. The acidic aqueous layer was neutralized with a slight excess of aqueous sodium hydroxide and extracted wih dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness, giving 56;5 g of the title compound as an oil having the expected NMR spectrum. Wile intermediate nitrile was used.wxthout further purification. Example 13 Preparation of racemic 2-(4-phenylphenyl)-2 (2-pyridyl)-4-[N,N-bis(1-methylethyl)amino]butanamide. i A mixture of 1.0 g (2.5 mmole) of the nitrile from Example 12 and 2 g of powdered potassium hydroxide in -10 ml of t-butyl alcohol was heated at reflux for about 12 hours. After cooling, the reaction mixture was treated with water and extracted with diethyl ether. The organic phase was dried over magnesium sulfate, filtered, and ¯concentrated to an oil. Crystallization from Skellysolve |B afforded the title compound (0.46 g) as a white solid. Structure assignment was supported by proton NMR and infrared spectra and by elemental analysis. : C H N NMR (CDC13) #ppm 0.88, 0.95, 7.0-7.75, 8.50, 8.55 Calc'd. 78.04 8.00 10.11 IR (CEC13) -3350, 2970, 1670 cm 1 Fd. 77.92 8.06 9.88 Example 14 Preparation of 5-(4-phenylphenyl)-5-[2-[N,N- bis(1-methylethyl)amino]ethyl]-1,3-diazabicyclo[4.4.0]oct-2en-4-one, Racemate C(III, X=phenyl). The title racemate, m.p. 2570-2580, was prepared by the methods of Examples 1 and 4 using the racemic amide of Example 13. Structure assignment was supported by nmr and infrared spectra and by elemental analysis. C H N Calc'd. 77.92 8.64 9.73 NMR(CDCl3)#ppm 0.79, 0.85, 0.88, 0.94, 7.05-7.65 Fd. 77.93 8.79 9.74 IR (CHC13) 2985, 1680, 1575 cm Example 15 Preparation of 5-(4-phenylphenyl)-5-[2-[N,N- bis(1-methylethyl)amino]ethyl]-1,3-diazabicyclo[4.4.0]oct-2en-4-one, Racemate D (III, X=phenyl). The title racemate is prepared by the methods of Examples 2 and 4 using the racemic amide of Example 13. Example 16 Preparation of 5-(-phenylphenyl)-5-12-IN,N- bis(1-methylethyl)amino]ethyl]-1,3-diazabicyclo[4.4.0]octan 4-one, Racemate C(V, X=phenyl). The title racemate was prepared by the method of Example 5 using Racemate C(III, X=phenyl) (of Example 14). Structure assignment was supported by the nmr, infrared, and ultraviolet spectra and by elemental analysis. C H N Calc'd. 77.56 9.06 9.65 NMR(CDC13) dppm 1.02, 1.05, 1.10, 1.13, 7.05-7.65 Fd 77.11 9.03 9.74 IR (CHCl3) 3400, 2960, 1660 cm-1 v(MeOH) #max 254mm Example 17 Preparation of 5-(4-phenylphenyl-5- 2- [N,N-bis(1-methylethyl)amino] ethyl] -1,3-diazabicyclo [4.4.0] octan-4-one, Racemate D (V,X=phenyl). The title racemate is prepared by the method of Example 5 using Racemate D (III, X=phenyl) (of Example 15). Example 18 Preparation of 5-(2-chlorphenyl)-5- [2- [N,N-bis(1-methylethyl)amino] ethyl] -1,3-diazabicyclo L4.4.03 oct-2-en-4-one, Racemate E (III, X=chloro). The title acetate, m.p.154-1560, was prepared by the methods of Example 1 and 4 using 28.5 g (76 mmole) of racemic 2-(2-chlorophenyl)-2-(2-pyridyl)-4-[N,N-bis (1-methylethyl)amino]butanamide. C H N C1 calc'd. 67.76 8.27 10.78 9.09 NMR(CDC13) fippm 0.90, 0.95, 0.98, 1.03, 7.05-7.45 Fd. 67.90 8.28 10.54 9.10 IR(CHCl3) 2960, 1680, 1580 cm v(MeOH) #max 273-4mm Example 19 Preparation of 5-(2-chlorophenyl)-5-[N,N- bis(1-methylethyl)amino]ethyl]-1,3-diazabicyclo]4.4.0]oct2-en-4-one, Racemate F(III, X=chloro). The title racemate is prepared by the methods of Examples 2 and 4 using racemic 2-(2-chlorophenyl)-2-(2-pyridyl)-4 [N,N-bis(1-methylethyl)amino]butanamide. Example 20 Preparation of 5-(2-chlorophenyl)-5-[2-[N,N- bis(1-methylethyl)aminolethyll-1,3-diazabicyclol4.4.0 octan-4-one, Racemate E(V, X=chloro). The title racemate, m.p. 232-235 , was prepared by the method of Example 10 using Racemate E(III, X=chloro) (of Example 18). Structure assignment was supported by nmr, infrared, and ultraviolet spectra and by elemental analysis. C H N C1 Calc'd. 67.41 8.74 10.72 9.04 NMR(CDCl3) #ppm 1.01, 1.09, 7.05-7.65 Fd. 67.46 8.93 10.40 8.76 IR(CHCl3) 3410, -1 2970, 1670 cm Example 21 Preparation of 5-(2-chloropfienyl)-5-f2-IN,N- bis(1-methylethyl)amino]ethyl]-1,3-diazabicyclo]4.4.0] octan-4-one, Racemate F(V, X=chloro). The title racemate is prepared by the method of Example 10 using Racemate F(III, X=chloro) (of Example 19). Example 22 Table 1: Preparation of Substituted 1,3-Diazabicyclo [4.4.0]oct-2-en-4-ones. EMI23.1 Examples for Example for Amide X 1 Racemate Methods Used* Precursor (II) H Phenyl G 4 or 8 1 H H Phenyl H 6 or 9 2 4-Phenyl Methyl K 4 or 8 13 4-Phenyl Methyl L 6 or 9 13 4-Phenyl Phenyl M 4 or 8 13 4-Phenyl Phenyl N 6 or 9 13 2-Chioro Methyl P 4 or 8 it 2-Chloro Methyl Q 6 or 9 * 2-Chloro Phenyl R 4 or 8 it 2-Chloro Phenyl S . 6 or 9 * *All methods require use of dialkyl ketal of appropriate amide Rl-CON(Alkyl)2. Variations on the syntheses use similar orthoesters or active methylene compounds of general type R1-CX3, where X=OAlkyl, N(Alkyl)2 (or combinations thereof), and the like. XPrecursor: 2-(2-chlorophenyl)-2-(2-pyridyl)-4-[N,N-bis(1-methylethyl) amino]butanamide. Example 23 Table 2: Preparation of Substituted 1,3 Diazabicyclo[4.4.0]octan-4-ones from compounds of Table 1. EMI24.1 Examples for X R1 Racemate Methods Used H Phenyl G 5 or 10 H Phenyl . H H 7 or 11 4-Phenyl Methyl K- 5 or 10 4-Phenyl Methyl L 7 or .11 - 4-Phenyl Phenyl N M 5 or 10 4-Phenyl Phenyl N 7 or 11 2-Chloro Methyl P 5 or 10 2-Chloro Methyl Q 7 or 11 2-Chloro Phenyl R 5 or 10 2 Chloro Phenyl S 7 or 11 Example 24 EMI25.1 To 0.26g (5.5 mmoles) of 50% sodium hydride mineral oil dispersion, previously washed with Skelly B to remove the mineral oil, in 25 ml of DMF was added 1.63g (4.6 minoles) of Racemate A of Example S and the reaction mixture was stirred at room temperature for 15 minutes. After this time 0.97 g (6.8mmoles) of methyl iodide was added to the reaction mixture and it was stirred for an additional 40 min. The excess sodium hydride was then destroyed with H2O before partitioning the reaction mixture between H20 and ether/ethylacetate(1:1). The organic phase was extracted 3 times with 1N SC1 solution and the acidic solution was backwashed once with ether. The aqueous acidic solution was basified with 5% sodium hydroxide solution and extracted wih ether. The ether extracts were dried over sodium sulfate. Solvent removal gave an oil which upon chromatography over silica gel using CHCl3/EtOH/NH4OH as the eluent afforded pure title compound of the above structure as an oil. C H N Calc'd 74.35 10.04 li.31 Fd. 74.35 10.22 10.80 NMR(CDCL3) dppm 1.00, 1.10, 3.03, 7.17-7.33 IR(CHCL3) 1650 cm-1 Example 25 EMI26.1 To 2.29g (12 mmoles) of cuprous iodide in 20 ml of dry tetrahydrafuren (THE) cooled to ca. -200C in an argon atmosphere was added dropwise 8.3 ml of 2.9N methyl magnesium chloride/THE (24 mmoles). After stirring for 10 minutes, 2.84 g (8 mmoles) of Racemate A of Example 4 in 60 ml of THE was added dropwise at the above temperature. After addition the reaction mixture was stirred for an' additional hour and then allowed to warm to room temperature where it was also stirred for on hour. After cooling to 0 C, in HCL solvent was added until the solution attained a pH of 3. After stirring for 30 minutes the solution was basified with a potassium hydroxide solution to pH 12 and the two layers were separated. The aqueous phase was extracted with additional portions of ether and the combined extracts were washed three times with 3% NH4OH solution followed by saturated sodium chloride solution. The solution was then dried over sodium sulfate and upon solvent removal a pale yellow solid remained. Chromatography of this residue over silica gel using CH2Cl2/EtOH/NH4OH(85:14:1) as an eluent afforded the pure compound melting at about 142-145 C of the above structure. C . H N Calc'd 74.35 10.04 11.31 Fd 73.97 10.05 11.22 N:MR(CDC/3) #ppm 0.85, 0.87, 0.94, 0.96, 1.08, 1.14, IR (CHC/3) 3400, 1665 cm-1 CHART A EMI28.1

Claims: Claims: 1. A compound of the forumla: EMI29.1 wherein R1 is: a) hydrogen; b) alkyl of from 1 to 6 carbon atoms, inclusive; or c) phenyl wherein Y is: a) hydrogen; or b) EMI29.2 wherein each X is a substituent taken independently, selected from the group consisting of: a) hydrogen; b) halogen; c) alkyl of from 1 to 6 carbon atoms, inclusive; d) alkoxy of from 1 to 6 carbon atoms, inclusive; or e) phenyl; wherein Z is: I a) hydrogen; b) b) (CH2)n-NR2R3, wherein n is 1 to 6. wherein R2 and R3 are: a) alkyl of from 1 to 6 carbon atoms, inclusive R2 and R3 each being the same or different ; or wherein R2 and R3 are taken together to form a cyclic structure either-saturated or unsaturated of from 4 to 6 carbon atoms, inclusive; wherein R4 is: a) hydrogen; or b) alkyl o 1 to 6 carbon atoms, inclusive; and the pharmacologically acceptable salts. 2. A compound according to Claim 1 wherein R1 is hydrogen. 3. 3. 1,3-diazabicyclo[4.4.0]oct-2-en-4-one, and the corresponding isomers and racemates thereof, compounds according to Claim 2. 4. 5-phenyl-5-l2-lN,N-bis(l-mebhyletllyl)2millo]ethyl]- 1,3-diazabicyclo[4.4.O]octan-4-one, and the corresponding isomers and racemates thereof, compounds according to Claim 2. 5. 5-(4-phenylphenyl)-5-[2-[N,N-bis(1-methylethyl)amino]ethyl]-1,3-diazabicyclo[4.4.0]oct-2-en-4-one, and the corresponding isomers and racemates thereof, compounds according to Claim 2. 6. 5-(4-phenylphenyl)-5-[2-[N,N-bis(1-methylethyl)amino] ethyl]-1,3-diazabicyclo[4.4.0]octan-4-one, and the corresponding isomers and racemates thereof, compounds according to Claim 2. 7. 5-(2-chlorophenyl)-5-[2-[N,N-bis(l-m2thylethyl)anino3 ethyl]-1,3-diazabicyclo[4.4.0]oct-2-en-4-one, and the corresponding isomers and racemates thereof, compounds according to claim 2. 8. 5-(2-chlorophenyl)-5-[2-[N,N-bis(1-methylethyl)amino] ethyl]-1,3-diazabicyclo[4.4.0]octan-4-one, and the corresponding isomers and racemates thereof, compounds according to Claim 2. 9. A compound according to Claim 1 wherein R1 is alkyl of from 1 to 6 carbon atoms, inclusive. 10. 2-methyl-5-phenyl-5-[2-[N,N-bis(1-methylethylamino] ethyl]-1,3-diazabicyclo[4.4.0]oct-2-en-4-one, and the corresponding isomers and racemates thereof, compounds according to Claim 9. ;11, 2-methyl-5-phenyl-5-t2-[N,N-bis(1-methylethyleamino] ethyl]-1,3-diazabicyclo[4.4.0]octan-4-one, and the corresponding isomers and racemates thereof, compounds according to Claim 9. 12. 2-methyl-5-(4-phenylphenyl)-5-[2-[N,N-bis(1methylethylamino]ethyl]-1,3-diazábicyclo[4.4.0]oct-z-en-4one, and the corresponding isomers and racemates thereof, compounds according to claim 9. 13. 2-methyl-5-(4-phenyiDhenyl)-5-[2-[N,N-bis(l-methyl- ethylamino]ethyl]-1,3-diazabicyclo[4.4.0]octan-4-one, and the corresponding isomers and racemates'thereof, compounds according to claim 9. .14. 9-methyl-5-(2-chloropnenyl)-5-[2-lN,N-bisfil-methyl- ethylamino]ethyl]-1,3-diazabicyclo[4.4.0]oct-2-en-4-one, and the corresponding isomers and racemates thereof, compounds according to claim 9. 15. 2-methyl-5-( 2-chlorophenyl)-5- [ 2- fN,N-bis( l-methyl- ethylamino]ethyl]-1,3-diazabicyclo[4.4.0]octan-4-one, and the corresponding isomers and racemates thereof, compounds according to claim 9. 16. A compound according to claim 1 wherein R1 is phenyl. 17. 2-phenyl-5-phenyl-5-[2-N,N-bis(1-methylethylamino]ethyl]-1,3-diazabicyclo[4.4.0]oct-2-en-4-one, and the corresponding isomers and racemates thereof, compounds according to claim 16. 18. 2-phenyl-5-phenyl-5-[2-[N,N-bis(1-methylethylamino)ethyl]-1,3-diazabicyclo[4.4.0]octan-4-one, and the corresponding isomers and racemates thereof, compounds according to claim 16. 19. 2-phenyl-5-(4-phenylphenyl)-5-[2-[N,N-bis(1-methylethylamino]ethyl]-1,3-diazabicyclo[4.4.0]oct-2-en-4-one. and thecorresponding isomers and racemates thereof, compounds according to claim 16. 20. 2-phenyl-5-(4¯phenylphenyl)-5-[2-[N,N-bis(1-methyl- ethylamino]ethyl]-1,3-diazabicyclo[4.4.0]octan-4-one, and the corresponding isomers and racemates thereof, compounds according to claim 16. 21. 2-phenYl-5-(2-chlorophenyl)-5-l2-lNN-bis(l-methyl- ethylamino]ethyl]-1,3-diazabicyclo[4.4.0]oct-2-en-4-one, and the corresponding isomers and racemates thereof, compounds according to claim 16. 22. 2-phenyl-5-(2-ch.lorophenyl)-5-[2-[N,N-bis(l-methyl- ethylamino]ethyl]-1,3-diazabicyclo[4.4.0]octan-4-one, and the corresponding isomers and racemates thereof, compounds according to claim 16.

Inventors: ADELSTEIN, GILBERT WILLIAM, CHORVAT, ROBERT JOHN
Applicants: G.D. SEARLE & CO.
Application year: 1983
Main classification: C07D471
IPC codes: C07D471, C07D213, C07D211