METHOD FOR TREATMENT OR PROPHYLAXIS OF CARDIAC DISORDERS

Abstract: A method for the treatment or prophylaxis of cardiac disorders in a mammal, comprising administering to such mammal a short-acting ss-blocking compound of the formula: (FORMULA) wherein X is an ester-containing group; R may be lower alkyl, aralkyl or an ester-containing group; R<u1>u may be lower alkyl; and Ar may be substituted or unsubstituted aromatic; or a pharmaceutically acceptable salt thereof. Novel compounds possessing short acting ss-adrenergic blocking activity are also disclosed.

Description: METHOD FOR TREATMENT OR PROPHYLAXIS OF CARDIAC DISORDERS Backαround of the Invention The present invention relates to the treatment or prophylaxis of cardiac disorders. More particularly, the invention relates to a novel method of treatment or prophylaxis of cardiac disorders which comprises administration of β-adrenergic blocking agents and to compounds useful in such method. The therapeutic and prophylactic- uses of compounds which block sympathetic nervous. stimulation of S-adrenergic receptors in the ' eart, lungs, vascular system and other organs are well documented. Typically, such compounds are administered therapeutically to patients suffering from ischemic heart disease or myocardial infarction for the purpose of reducing heart work, i.e., heart rate and contractile force. Reducing heart work reduces oxygen demand, and may also actually increase oxygen supply. Thus reducing heart work can aid in the. pre¬ vention of further tissue damage and can relieve angina pectoris. β-Adrenergic stimulation may also aggravate or cause arrhythmias because of increased levels of c at ec hoi amines. Thus β-blocking agents may be employed to reduce the risks of arrhythmias. Compounds have been discovered which selectively block S-adrenergic receptors in various organs. Beta receptors in the heart are generally referred to as &-, receptors, and those associated with vasodilation and bronchodilation are S 2 receptors. Selective -e- blockers are preferred for the treatment of cardiac disorders because they may have Tεss ootεntial to cause hypertension or bronchoconstriction. A number of S-, selective adrεnergic blocking agents have been discovered. Smith, L.H. , ' . Appl . Chem. Biotechnol., 28, 201-212 (1978). Most of such compounds are structural variations of l-amino-3-aryloxy-2-propanol . Heretofore, the emphasis in β-blocker research has been to develop compounds which can be administered to cardiac patients over long periods of time. However, often it is desirable in the critical care setting to quickly reduce heart wDrk or improve rhythmicity during a cardiac crisis, e.g., during or shortly after a myocardial infarc¬ tion. Conventional β- blocking agents can be employed for such treat¬ ment, but their duration of action may be much longer than desired by the physician. A β-blocking agent possessing a long duration of action does not allow precise control of heart work or prompt reversal of the β-blocking effect, which may be required in a critical care setting. For instance, if heart output becomes dangerously low, it is desirable to quickly reduce or eliminate β-blocking activity. The lingering activity of available β-blocking agents can be counterproductive and can greatly complicate the therapeutic decisions required of the physician during ,such critical care of cardiac patients. Accordingly, there is a need for a pharmaceutical preparation and method of treatment, employing a β-adrεnergic blocking agent having a short duration of action. Summary of the Invention In accordance with the present invention, disclosed herein is a method for the treatment or prophylaxis of cardiac disorders in a mammal comprising administering to such marπrcal a short-acting β-blocking compound of the formula: OH Ar-X-CH-CH~-N-R ~ H 0 0 0 0 0 wherein X may be -0-C -, -R.--0-C-, -0-C-R,-, -R, -0-C-R,-, -C-0-R-,-, -R,-C-0-R,-; R may be lower alkyl, lower alkenyl or aralkyl; R, may be lower alkyl; and Ar may be unsubstituted aromatic or aromatic substituted with lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halogen, aceta ido, amino, nitro, alkyl amino, hydroxy, hydroxy- alkyl, cyano, or a group of the formula 0 R 2 -0-C-(CH 2 ) n - wherein R 2 is lower alkyl, aryl or aralkyl and n is an integer from 0 to about 10; or a pharmaceutically acceptable salt thereof. Detailed Description of the Invention Compounds administered by the method of the present invention are represented by the formula: - OH Ar-X-CH-CH,-N-R 0 0 II II wherein X represents an ester function of the formula -0-C-, -R j -O-C-, 0 0 0 0 -0-C-R-^-, -R-^O-C-R---, -C-O-rR-,-, -Rj-C-O-R,-; R represents lower alkyl of straight and branched carbon chains. from 1 to. about 10 carbon .atoms; cycloalkyl of from 3 tα 7 carbon atoms; alkenyl of from 3 to 10 carbon atoms, aralkyl or aryloxyalkyl wherein the alkyl portion contains from a ' bout 1 to about 5 carbon atoms and the aryl portion represents sub¬ stituted or unsubstituted monocyclic or polycyclic aromatic or hetεro- cyclic ring systems of from 6 to about 10 carbon atoms, such as 3,4-dimethoxyphenethyl, 4-carbamoylphenoxyethyl, l,l-dimethyl-2-(3- indolyl) ethyl and the like; R, represents lower alkyl of from 1 to about 5 carbon atoms, and Ar represents substituted or unsubstituted aromatic, including monocyclic, polycyclic and heterocyclic ring systems. When two or more groups of the same designation occur in the same formula, it is not necessary that those groups be identical. Aromatic (Ar) substituents may include lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halogen, acetamido, amino, nitro, lower alkyl ami no, hydroxy, hydroxyalkyl , cyano, and groups of the formula 0 * 2 -0-C-(CH 2 ) n - wherein R 2 is lower alkyl, aryl or aralkyl ~~ ά n is an integer from 0 to about 10. The compounds described herein are not limited to any particular stereoisomeric configuration. Such compounds may be administered as their pharmaceutically acceptable acid addition salts, e.g., as the hydrochloride, sulfate, phosphate, oxalate, gluconate, tartrate, etc. 5 In preferred compounds, R is lower alkyl of from 1 to about 5 carbon atoms, such as isopropyl, t-butyl; or aralkyl wherein the alkyl portion contains from 1 to about 3 carbon atoms, and the aryl portion contains from 6 to about 10 carbon atoms, such as 3,4-dimethoxy- 10 phenethyl; R, is methylene; and Ar is unsubstituted phenyl, or phenyl substituted with lower alkyl of from 1 to about 5 carbon atoms, fluoro, chloro, nitro, or a group of the formula .0 R 2 -0-C-(CH 2 ) n - 15 wherein R 2 is lower alkyl of from 1 to about 5 carbon atoms and n is an integer from 0 to about 5. In particularly preferred embodiments of the 0 II present invention, X is -C-0-CH 2 -; R is selected from the group consisti ng of i sopropyl , t-butyl , and 3 ,4-d ' imethoxyphenethyi ; and Ar is 20 unsubstituted phenyl or phenyl substituted wi th methyl , fluoro, chl oro , or nitro. In an al ternative embodiment, the ami ne substituent, R, may al so -- include ester-containi ng groups. For instance, R may be of the formul a 0 -2-C-0-R, wherein 2 ia a straight or branched chain hydrocarbon of from 1 to about 30 10 carbon atoms. The compounds described herein may be prepared by a number of synthetic methods-, depending upon the particular structure desired. Four reaction schemes are described for various configurations of the 35 ester function, X. For compounds of the formulas hereinbefore described in which X 0 0 II II is -0-C- or -0-C-R,-, the following reaction scheme may be employed: 0 OH H0-C-R 1 -CH-CH 2 C1 + H 2 N-R 0 OH H0-C-R,-CH-CH«-N-R 1 L H (I) OH (I) + ArOH Ar-0-C-R,-CH-Q-L-N-R 1 H In the above scheme, R, is eliminated when X is -0-C-. Suitable, protective groups are advantageously reacted with the hydroxyl or amino groups as is well ' known in the art. For example, the amino group of compound I may be reacted with p-methoxybenzyloxy- carbonyl azide to form the N-p-methoxybenzyloxycarbonyl derivative, and the hydroxy acid may be reacted with dihydropyran followed by selective cleavage of the tetrahydropyranyl ester to yield the free acid. The protective groups may be cleaved from the aryl compound, e.g., by treat¬ ment with a mineral acid. 0 0 II For compounds in which X is -R,-0-C- or -R^O-C-R^, the following reaction scheme may be employed: 0 OH HO-C-R TT-CH-N-R + Ar-R, -0H H 0 II * GH Ar-R O-C-R* CH-CH„-N-R 0 II 'el imi nated when X i s -R.- -0-C- Compounds i n whi ch Ar is not substituted with an ester-contai ni ng 0 0 II It group and in which X is -C-O-R,- or -R,-C-0-R,- are advantageously prepared by either of the following two schemes: Ar-R * *-SC-Cl + HO-R 1 -CHA-CH 2 0 OH *eliminated when X is -C-O-R.,- . This latter scheme is particularly preferred for compounds in which R is an ester-containing group. The compounds of this invention are advantageously administered parenterally, e.g., by intravenous injection or intravenous infusion. Formulations for intravenous injection preferably include the active compound as a soluble acid addition salt in a properly buffered isotonic solution. The dosage administered to a patient and the duration of infusion will depend upon the patient's needs and the particular compounds employed. For sjiort periods of infusion, e.g. less than about three hours, the duration of effect is thought to be determined by both metabolic effects and distribution phenomena. For relatively long periods of infusion, e.g. greater than about three hours, the duration of effect is thought to depend largely on metabol c effects. Accordingly, although the present methods and compounds are generally useful for short term infusion therapy, certain compounds are preferred for longer durations of infusion. This principle is demonstrated by reference to the 40 minute and three hour infusion studies described in Examples LXXX-CIV. The compounds have been found to be generally non- toxic within conventional dosage ranges. Dosages of from about 0.001 to about 100 mg. per kg. of body weight per hour are generally employed, with preferred dosages ranging from about 0.01 to about 10 mg. per kg. of body weight per hour. The compounds of the present invention have a relatively short duration of action compared to conventional β-blockers. Jji v tro studies in human whole blood indicate that the ester functions are subject to rapid enzymatic cleavage, resulting in inactive metabolites. Compounds of the present invention in which the amine substituent, R, contains an ester function, have two potentially labile sites for enzymatic hydrolysis. Thus the β-blockiπg activity can be carefully controlled by regulating dosage size and rate of administration. The time required for substantially complete disappearance of the β-blocking effects of the compounds of 'the present invention ranges from about 5-10 minutes to about 1 hour or more. Generally, it is preferred that the recovery is accomplished within about ten to fifteen minutes. A short acting β-blocker can advantageously be infused at a rate sufficient to provide the desired action, e.g., titrated to the specific patient's needs, and such action can be promptly discontinued by stopping the infusion. Thus, the method of the present invention provides a very useful therapeutic alternative in the treatment or prophylaxis of cardiac disorders. The present invention is ' further illustrated by the following examples which are not intended to be limiting. _ Example I This example describes the synthesis of a compound of the following formula: -CH 2 -CH 2 - . HCl 3-[(3,4-Dimethoxyohenethyl) amino] -2-hydroxyprop ionic Acid A mixture of 20g (0.16 mole) of β-chlorolactic acid and 86g (0.48 mole) of 3,4-dimethoxyphenethylamiπe was heated at 110°C for 15 hours. The resulting product was dissolved in about 200 ml of water and the pH was adjusted to about 8 with The aqueous section was extracted with 2x500 ml of chloroform and neutralized to pH 7 with diluted HCl. The solution was evaporated to dryness and the residue was re- crystallized in EtOH to give 24.5g (61.5%) of crystals: m.p. 187.5- 188.5°C. The NNR, IR and mass spectra were consistent with the assigned structure, and the elemental analysis was consistent with the empirical formula, C^gH-^gOgN. 3-[[N-(3,4-Dimethoxyphenethyl)-N-(4-methoxybenzyloxycarboπyl)l amino] -2-hydroxyprop ionic Acid. To a solution of 0.245g (0.91 mmole) of the amino acid from the previous experiment in 10 ml of dioxane-H D (1:1) was added 0.23g ' (2.73 mole) of NaHC0 3 and 0.19g (0.92 mmole) of p-methoxybenzyloxycarbonyl azide. The reaction mixture was stirred at room temperature for 16 hours and extracted between 20 ml of water and 2x20 ml of ether. Evaporation of the ether gave 0.08g (36%) of the product. The Nf-R and IR spectra were consistent with the assigned structure. 3-[ [N-(3,4-Dimethoxyphenethyl)-N-(4-methoxybenzyloxycarbonyl )] amino] -2- πtetrahydro-2-pyraπyl )oxy] propionic Acid. To 3.6g (8.9 mmole) of the α-hydroxy acid from the previous experiment in 20 ml of methylene chloride was added 3.74g (44.5 mmole) of dihydropyran and a catalytic amount of p-toluenesulfonic acid. The reaction mixture was stirred at room temperature for 3 hours and neutral zed with concentrated NH.OH. The reaction mixture was filtered and the solvent was evaporated. The residue was stirred with 70 ml ether and 0.3 ml of HCl at room temperature for 1 hour, neutralized with NH.OH, filtered, and the ether was removed jn_ vacuo to afford 3.92g (90.1%) of product. The NMR and IR spectra were consistent with the assigned structure. Phenyl 3-[[N-(3,4-Dimethoxypheπethyl )-N-(4-methoxybenzy1oxycarbony1 )] - amino] -2-f (tetrahydro-2-pyranyl )oxy] propioπate. A solution, which consisted of 3.92g (7.5 mmole) of the acid from the previous experiment, 30 ml of THF and 1.48g (9 mmole) of car- bonyldiimidazole was stirred at room temperature for 0.5 hour. To the reaction mixture was added 0.855g (10.5 mmole) of phenol and a catalytic amount of sodium i idazole. The reaction mixture was stirred for 10 hours and partitioned between 2x100 ml of ether and 100 ml of water. Evaporation of the ether gave an o l which was purified by column chromatography (silica gel/EtOAc: hexane=l:l) to give l.lg (24%) of oily product. The NMR and IR spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula CggHggOgN. N-(3,4-Dimethoxyphenethyl )-N-[(2-hydroxy-2-phenox.ycarbonyl )ethyl-j ' a ' ine Hydrochloride. - A mixture -of lg of the propionate from the previous experiment and 50 ml of 2% HCl in ether was stirred at room temperature for 2 hours. The precipitate was collected by filtration and recrystallized in 2-propanol to give 0.3g (46.6%) of white crystals: m.p. 150.5-151°C. The NMR, IR and MS spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula C ιg H 24 0 5 NCl. Examples II - IV The compounds described in the following table were produced by substantially the same procedure as that described in Example I, except that the aryl hydroxy reactants shown in Table I were substituted for phenol. The reaction products were purified by recrystallization from 2-propanol, to yield the indicated products which were identified by NMR and IR spectroscopy, elemental analysis, and melting point. Tablel 0 OH Ar-0-C-CH-CH 2 -N-CH 2 -CH 2 / A OCH, HC1 OCH, Example Ar-OH Ar Melting Point Example V This example describes the synthesis of a compound of the following formula: 2 -Methoxybenzyl 3-[[N-(3,4-Dimethoxyphenethyl)1 amino] -2-hydroxy- propi onate To 3g of the 3-(3,4-dimethoxyphεnethyl )amiπo-2-hydroxypropionic acid prepared in Example I was added 200 ml of benzene and 20 ml of 2- ethoxybenzyl alcohol. About 0.5 ml of concentrated HCl was added to catalyze the reaction. The reaction mixture was heated to reflux for 6 hours and the water was collected by a r.oisture trap. The reaction mixture was extracted with 200 ml of 0.5% HCl in water. The aqueous layer was basified with NaHCOg and extracted with CHClg. Evaporation of the CHC1, gave an oily residue which after chromotography on a column (silica gel/Et 2 0:Et0H=5:l) gave lg (23%) of white solid: m.p. 79.5- 82.5°C. The NMR, IR and mass spectra were consistent with the assigned structure and " the elemental analysis was consistent with the empirical formula C^H^OgN. Example VI This example describes the synthesis of a compound of the formul : . HCl 2,3 Epoxypropyl Benzoate A mixture containing 14.8g (0.2 mole) of glycidol, 150 ml of anhydrous ether, 16g (0.4 mole) of pyridinε and 28g (0.2 mole) of benzoyl chlori-de was stirred at room temperature for 2 hours. The. . mixture was filtered and the ether was evciporated to leavε an oil. This oil was distilled to give 21g (60%) of colorless oil: b.p. 92°C/0.5 mm Hg. The NMR and IR spectra werε consistent with the assigned structure. [3-( Isopropyl ami no) -2-hydroxy]propyl Benzoate Hvdrochloride To lg of the epoxide from the previous expεriment was added lOg of isopropyl amine. The resultant solution was refluxed for 16 hours and evaporated to dryness. The oily residue was chromatographed on a column (silica gel/EtOH:CH 7 Cl 2 =1.5:3.5) to afford 0.35g (22%) of the product (free amine). The amine was converted to its HCl salt by addition of etheral HCl. The amine salt was collected by filtration and recrystallized in 2-propanol to give whitε crystals: m.p. 155.5- 156.5°C. The NMR and IR spectra were consistent with the assigned structure and the elemental analysis was consistent with " the empirical formula C^H O^NCl Examples VII - XIII The expεriment of Example VI was repeatεd in all εssential details to produce the compounds described in Table II, excεpt that thε rεactants dεscr bed in the second and third columns of the table were substituted for benzoyl chloride and isopropyl amine respectively? The compound of Examplε VIII was purifiεd by rεcrystallization from acetone, and the compound of Example IX was purified by recrystalliza- tion from toluene. All of the compounds werε prεpared as the hydro- chloridε salts except the compound of Example IX which was the free base. Each of the compounds was identified by NMR and IR spectroscopy, elemental analysis, and melting point. Table II 0 OH Ar-C-0-CH 9 -CH-CH 9 -N-R ~ H 0 Example Λr-C-Cl R-NII, Ar R Melting Point VII benzoyl chloride 3,4-dimethoxyphenethyl phenyl 3, -dimethoxyphenethyl 130°C amine VIII 3-meth lbenzoyl isopropylamine 3-methylphenyl isopropyl 137.5-138 υ C chloride IX 3-methylbenzoyl 3,4-dimethoxyphenethyl 3-methylphenyl 3, -dimethoxyphenethyl 08.5 C chloride amine X -methylbenzoyl isopropylamine -methylphenyl isopropyl 151.5-152°C chloride XI 4-mothy1 enzoyl 3, -dimethoxyphenethyl -meth lphenyl 3, -dimethoxyphenethyl 153-153.5°C chlori e amine XII 2-chlorobenzoyl isopropylamine 2-chlorophenyl isopropyl 129°C chloride Example XIV This examplε describes an alternate synthesis of thε compound in Example XII. 3-( Isopropyl ami no )-l, -propanediol A ixturε of 37g (0.5 mole) of glycidol and 35. g (0.6 mole) of isopropyl amine was stirred at 25° overnight. Excess isopropyl amine was evaporated in vacuo and the mixture was distilled to give 53g of prod¬ uct: b.p. 80°C/0.1mm Hg. The KM and IR spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula CgH,c0 2 N. [3-( Isopropyl ami no ) -2-hydroxy] propyl 2-chl orobεnzoatε hydrochl ori dε A solution of 10g (75 mmole) of the diol from the previous experiment and 5.9g (75 mmole) of pyridine hydrochloride in 20 ml of pyridine was treated with 13. lg (75 πrnole) of 2-chl orobenzoyl chloridε. • The mixture was stirred at room temperature for 2 hours and 100 ml of water was ad-ded. The Ryridioe was evaporated n vacuo .at 55-60°C and the aqueous solution was washed with 100 ml of ether. The aqueous layer was then basified with K-^CO, and extracted with methylene chloridε. The methyl εne chloride layer was acidified with ethεr-HCl and εvaporated to dryness. The residue was crystallized in 2-propanol to give 12.5g (54%) of product: m.p. 129°C. Examples XV - LI I I The experiment of Example XIV was repeated in all essential details to produce the compounds identified in Table III, except the reactants listed in the second and third columns of thε table were substituted for isopropyl mine and 2-chl orobenzoyl chloride respectively. The compounds were prepared as the acid addition salts or freε bases as indicated in Table III. Each of the compounds was identified by NR and IR spectroscopy, elemental analysis! and melting point. TABLE I I I 0 Oil Ar-C-0-CH 9 -CII-CH 9 -N-R Reactants 0 II Addition Crystal l ization Melting Example R-NII 2 Ar-C-CI Sal t Λr Solvent Point XV Isopropyl amine 1 -naphthoyl HCl 1-naphthyl Isopropyl 2-propanol 145 - 1 7 υ C \ chloride XVI Isopropyl ami no k~naphthoyl HCl 2-naphthyl Isopropyl 2-propanol 149.5-150 Q C ■ chloride XVII Isopropylamlne 2 -methyl benzoyl HCl 2 -methyl henyl Isopropyl 2-propanol 120.5-121.5°C 1 chloride 1 XVII I isopropylamlne 2-fluorobenzoyl HCl 2-fluorophenyl isopropyl 144-145°C chloride XIX Isopropyl mlne 3-fluorobenzoyl HCl 3 -f luorophenyl Isopropyl acetone/ether 122.5-123°C chloride XX Isopropylamlne 4 -f luorobenzoyl HCl 4 -f luorophenyl Isopropyl 2-propanol 139-110"C chlo ide 1 I XXI Isopropylamlne 3-nl trobenzoyl HCl 3-nl rophenyl Isopropyl 2-propanol 160-160.5°C chloride XXI I Isopropylamlne 4-n1trobenzoyl HCl 4-nltrpphenyl Isopropyl 2-propanol 203-205°C chloride TABLE III (Cpnt'd) 0 OH Λr-C-O-CIL-CH-CIL-N-R ~ ' ά H Reactants 0 Addition Crystallization Melting Example R-NII, Ar-C-Cl Salt Λr Solvent Point XXIII Isopropylamlne 4-methoxybenzoyl HCl 4-methoxyphenyl Isopropyl 2-propanol 139-140°C chloride XXIV Isopropylamlne 4-cyanobenzoyl HCl 4-cyanophenyl isopropyl 2-propanol 167.5-168 5 U C chloride XXV Isopropylamlne 2-allyloxybenzoyl oxalate 2-allyloxyphenyl Isopropyl 2-ρropanol 133.5-l35 υ C chloride XX I Isopropylamlne 3-al lyloxybenzoyl HCl 3-allyloxyphenyl Isopropyl 2-propanol/ether 111-112°C chloride XXVII isopropylamlne 2 -n-propyl oxybe nzoy 1 oxal ate 2-n-propyloxyphenyl Isopropyl 2-propanol 131.5-132.5 C chloride XXVIII Isopropylamlne 3-n-ρropyloxybenzoyl HCl 3-n-propyloxyphenyl Isopropyl 2-propanol/ether 120-120.5°C chloride XXIX Isopropylamlne -fo myl benzoyl oxal ate 4-formylphenyl isopropyl 2-propanol (hydroscoplc) chloride XXX Isopropylamlne -benzyloxybenzoyl HCl 4-benzyloxyphenyl "Isopropyl methanol 137-137.5"C chlor ide TABLE III (Cont'd) 0 OH. Λr-C-O-CIL-CH-CIL-N-R ~ <- II Reactants 0 Addition Crystallization Melting Example R-NH 2 Λr-C-Cl Salt Ar Solvent Point XXXI 3,4 dimethoxy¬ 2-methylbenzoyl oxalate 2 -meth l phenyl 3,4 -dimethoxy¬ ethanol/ 169-170°C phenethyl amine chloride phenethyl 2-propanol • XXXI I 3,4 -dime hoxy- 3 -chl orobenzoyl oxalate 3-chlorophenyl 3,4- lmethoxy- 2-propanol 183-106°C phcncthylamlnc chloride pheneth l XXXI 11 3, 4 -dimethoxy¬ 2-f luorobenzoyl HCl 2-f tuorophenyl 3,4-dlmethoxy- 2-propanol/ 109-110°C phenethyl amino chlori e phcne hyl ether 1 ! XXXIV 3,4 -dimethoxy¬ 3-fluorobenzoyl ι oxalate 3-fluoropl\enyl 3,4-dlmethoxy- 2-propanol 171-171.5°C phenethyl a ine chlori e phenethyl XXXV 3, -dimethoxy¬ -f luorobenzoyl HCl -fluorophenyl 3,4-dlmethoxy 2-propanol 154-154.5°C phenethyl amine chloride phenethyl XXX 1 3,4 -dimethoxy¬ 4-nltrobenzoyl HCl 4-nl rophenyl 3,4-dlmetlloxy- 2-propanol 162-163°C pheneth l am tne chloride pbenethyl * XXXVII t-butylamlne benzoyl free base phenyl t-butyl CC hexane 105-106°C chloride XXXVIII t-butyl amine 2 -chl orobenzoyl free base 2-chloropbenyl t-butyl CC1, 74.5-75.5°C chloride TABLE I I I (Cont'd) 0 OH . Ar-C-0-CH-,-CH-CI -N-R Reactants 0 Addi tion Crystallization Melting Example R-NH 2 Ar-C-Cl Sal t Ar Solvent Point XXXI X t-butylam1ne 2-f luorobenzoyl free base 2 -fluorophenyl t-butyl ccι 4 97.5-98"C chloride XL t-butylamlne 4-fluorobenzoyl free base -f luorophenyl t-butyl CCI ./hexane 109-110°C chlor ide XL I t-butyl amine 2 -methyl benzoyl free base 2-methylρlιenyl t-butyl CCl^/hexane 93-94°C chloride XLI I t-butylamlne 3 -methyl benzoyl free base 3 -methyl henyl t-butyl CCI./hexane 72-73°C chloride XLI II t-butyl amine 3-nltrobenzoyl free base 3-nitrophenyl t-butyl ccι 4 91-92°C chloride XL IV t-butyl Ine 4-nltrobonzoyl free base 4-nl trophenyl t-butyl CCI ./hexane 106-107°C chloride XLV t-butyl ami no 2-methy -nl ro- HCl 2-methyl-4-n1tro- t-butyl 2-propanol 170-171°C benzoyl chloride phenyl XLV I t-butylamlne 2-benzyloxybenzoyl free base 2 -benzyl oxyphenyl t-butyl chloride TABLE III (Cont'd) 0 Oil Λr-C-0-CH-,-CH-CI -N-R - ' L II Reac i ants 0 Addition Crystallization Melting Example R-NH 2 Ar-C-Cl Salt Ar R Solvent Point XLV 11 t-butylamine 3 -benzy 1 oxybe nzoy 1 free base 3 -benzyl oxyphenyl t-butyl CCl./hexane 100-101°C chloride XLVIII t-butylamlne 4 -benzyl oxybe nzoy 1 oxalate 4 -benzyl oxyphenyl t-butyl methanol 173-174°C chloride XL1X t-butyl a ine 4-allyloxybenzoyl oxalate 4-allyloxyphenyl t-butyl 2-propanol 139-139.5°C chloride L t-butylamlne 4-n-butyloxy- heml- 4-n-butyloxy- t-butyl 2-propanol 196-197°C benzoyl chloride oxalate phenyl LI t-butyl a ine 1-naphthoyl oxalate 1-naphthyl t-butyl 2-pr *>anol 165-166°C chloride LII t-butylamlne -fonnyl benzoyl oxalate 4-formylρhenyl t-butyl 2-propanol/ 170-171°C chloride ether LIII t-amyl mine 2-fluorobenzoyl free base 2 -fluorophenyl t-amyl ccι 4 50-51°C chloride Example LIV This example describes the synthesis of a compound of the formula @2-Hydroxy-3-(isopropylaminoHoropyl 4-aminobenzoate hydrochloride To 20 mg of 10% Pd-C in 30 πt of methanol was added 0.4g of the compound of Example XXII. The reaction vessel was kept under 30 p.s.i. of hydrogen and agitated for 1 hour. The catalyst was filtered and the methanol evaporated to give a solid, which was recrystallized in 2-propanol to give 220 mg (55%) of product: m.p. 211-212°C. The NMR and IR spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula C 13 H 21 N 2 0 3 C1. Examples LV-LXI The experiment of Example LIV was repeated in all essential details to produce the compounds identified in Table IV, except the starting materials described in the table were substituted for "the compound of Example XXII. Each of the compounds was identified by NMR and IR spectroscopy, elemental analysis, and melting point. O m ~\ Z. .y TABLE IV Starting Material Addition Crystallization Melting Example (Example No.) Ar R Salt Solvent Point LV XXI 3-aminophenyl isopropyl MCI 2-propanol 1 1-14 °C LVI XXX 4-hydroxyphenyl Isopropyl free base 2-propanol/ 170-170.5° methanol LVII XLII1 3-a inophenyl t-butyl oxalate 2-propanol 159.5°C LVIII XLV 2 -methyl - -ami no - t-butyl HCl 2-propanol/ 209-210°C phenyl ether LIX XLV I 2-hydroxyphenyl t-butyl hθiil oxalate methanol 200-208.5° LX XLV II 3-hydroxyphenyl t-butyl he ioxalate methanol/ 220-221°C acetone LXI XLVIII 4-hydroxyphenyl t-butyl hemioxalate 2-propanol/ 220-220.5° methanol Example LXII This example describes the synthesis of a compound of the formula [ 2 -Hydrox -3 -( isopropyl amino)] propyl 4-(acetamido) benzoate hydrochloride To lg (3.5 mmole) of the amine obtained in Example LIV in 30 mL of dried pyridine was added 0.32g (4.55 mmole) of acetyl chloride. After stirring at room temperature for 2 hours the pyridine was evaporated in vacuo. The residue was partitioned between 5% K 7 CO3 anc * methylene chloride. The methylene chloridε layer was acidified with ether-HCl and evaporated to dryness to give a gummy solid which was crystallized in acetone to give 0.38g (33%) of product: m.p. 195°C. The NMR and IR spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula C^H^N-O^Cl. Example LXIII The process in Example LXII was repeated in all essential details with the compound of Example LV as starting material and-thus produced the compound: [2-Hydroxy-3-(isopropylamino)] ropyl 3-(acetamido)- benzoate oxalate; m.p. 130-132.5°C. Example LXIV This example describes the synthesis of a compound of the formula CH 3 ) 2 [2-Hydroxy-3(isopropylamino)]prcpyl 4-(hydroxymethyl)benzoate hydrochloride To a solution of 5.4g (20.4 mmole) of the compound of Example XXIX in 20 mL of ethanol at 0°C was added 0.8g (20.4 mmole) of sodium borohydride. The reaction mixture was stirred at 0°C for 10 minutes and excess hydride was destroyed by addition of water. The ethanol was evaporated to dryness and the residue was partitioned between 1% K 2 C0 3 and methylene chloride. Evaporation of the methylene chloride gave an oil which was chromatographed on an alumina column using 10% ethanol in methylene chloride as the elutiπg solvent to give 32 mg (5%) of the product: m.p. 98-98.5°C. The NMR and IR spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula C-^H^NO^. Example LXV This example describes the synthesis of a compound of the formula 3-[N-(n-propyl)-N-benzyl] amino-l,2-propanediol A mixture of 74g (1 mole) of glycidol and 149g (1 mole) of N-benzyl-N-isopropyl amine was stirred at 25°C overnight. Distillation of the mixture gave 175.4g (79%) of product: b.p. 135°C/0.5 mm Hg. [3- [N-Beπzyl-N-(n-propyl)]^mino-2-hydroxy] propyl 4-πitrobeπzoate The diol from the previous experiment was allowed to react with p- nitrobenzoyl chloride m in a similar manner, as described in, the preparati-on of [2-Hydroxy-3-(isopropylamino)] propyl 2-chl orobenzoate hydrochloride in Example XIV. The product was purified by chromatography (silica gel/ether: hexane - 4:2). Yield was 65%. [2-Hydrox.y-3-(n-propyl)amino]propyl 4-aminobeπzoate oxalate The amine 12g (33 mmole) from the previous experiment was mixed with 50 mL of 2-propanol -ethanol (1:1), 2.97g (33 nmole) of oxalic acid and 0.24g of 10% Pd-C. The reaction vessel was pressurized with 50 p.s.i. of H 2 and agitated for 15 hours at room temperature. The reaction mixture was filtered. Evaporation of the 2-propanol from the filtrate resulted in crystallization of the product; 2.4c (22%): m.p. 173°C. The NMR and IR spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula c i5 H 22 N 2°7" Examole LXVI This example describes the synthesis of a compound of the formula 3-[N-[(4-methoxybeπzyl)oxycarbonyl] -N-(3,4-dimethoxyphenethyl)] ami no-1 , 2-propanedi ol A mixture of 25g (0.102 mole) of 3-(3,4-dimethoxyphenethyl)amino- 1,2-propanediol, 29g (0.345 mole) of sodium bicarbonate and 24g (0.116 mole) of p-methoxybenzyloxycarbonyl azide in 200 mL of dioxane and 10 mL_ of water was stirred at room temperature for 24 hours. After evapora¬ tion of the dioxane in vacuo, the residue was partitioned between water and CHC . Evaporation of CHC gave an oil which was purified by chromatography (silica gel/10% ethanol in methylene chloride) to give 13g (30.5%) of product. [2-H «ydro ' xy-3-[{N-[(4-Methoxybenzyl)oxycarbonyl]-N-(3,4-dimethoxy- * * phenethyl )] ami no] propyl 4-f ormyl benzoate . The diol from the previous experiment was allowed to react with 4-formylJDenzoyl chloride in a similar manner as described in the pre¬ paration of [2-Hydroxy-3-( isopropyl amino)] propyl 2-chl orobenzoate hydrochloride in Example XIV. The product was purified by chromatography (silica gel/2% ethanol in ether)'. The yield was 27%. [2-Hydroxy-3-[(3,4-dimethoxyphenethyl)amiπo]propyl 4-(hydroxymethyl) benzoate oxalate " The aldehyde obtained from the previous experiment was reduced by sodium borohydride in a similar manner as described in Example LXIV. The crude product was dissolved in ether-HCl and stirred at room temperature for 2 hours. The ether was evaporated to dryness and the product was partitioned between 5% K 2 C0 3 and methylene chloride. A solution of oxalic acid in 2-propanol was added to the methylene chloride layer and the precipitate was recrystallized in ethanol to give the desired product in 19% yield; m.p. 154-154.5°C._ The NMR and IR spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula C 23 H 29 N0 10 * Example LXVII The experiment of Example I is employed to produce a compound of the formula 0 OH -CH(CH 3 ) 2 The procedure is repeated in all essential details, except 4-hydroxy-5-chloropεπtanoic acid is substituted for B-chlorolactic acid and isopropyl amine is substituted for 3,4-dimethoxyphenethylamine to produce the intermediate 5-isopropyl mino-4-hydroxypentanoic acid. The hydroxy and amino groups are protected as described in Example I. The resulting acid is reacted with 1-naphthol instead of phenol and the protecting groups are removed as in, Example 1. The resulting compound should be a short acting β-blocker Example LXVIII The experiment of Example V is employed to produce a compound of the formula The procedure is repeated in all essential details, except -hydroxymethyl pyridine is substituted on a molar basis for 2- ethoxybenzyl alcohol. The product should be a short acting 8-blocker. TABLE V Test Compound (Numerical designation indicates previous example which describes preparation of compound) pA, Cardioselectivity Example Atria Trachea K β (Trachea)/K β (Atria) LXIX VI 6.3 7.2 -7 LXX XVIII 6.6 7.1 -3 LXXI , XII 6.8 7.4 -4 LXXII XXVII 6.6 — | 1 LXXIII XIX 6.5 7.0 -3 LXXIV XXI 6.8 7.2 -2.5 LXXV LV 6, 4 6.0 -2.5 LXX I VIII 6.0 7.3 -3 LXXV11 XX 6.6 7.3 -5 LXXVIII XXII 6.1 6.2 1 I.XXIX X 6.0 6.0 1 TABLE V (Cont'd) Test Compound (Numerical designation indicates previous example which describes preparation of compound) pA 5 Cardioselectivity Example Atria Trachea K B (Trachea)/K β (Atria) LXXX XXIII 6.0 6.3 -2 LXXXl XXIV 5.7 5.7 1 LXXXII L I 6.0 7.2 -2.5 LXXXIII LXIV 6.2 6.3 1 LXXXIV LXII 5.0 5.2 4 LXXXV XXX <6.0 — LXXXVI XXXVII 6.0 7.7 -0 LXXX II XXXIX 6.0 8.0 -16 LXXXVIII XXXVIII 7.2 7.0 -4 LXXXIX LIII 6.0 __ XC VII 7.0 6.3 TABLE V (Cont'd) Test Compound (Numerical designation indicates previous example which describes preparation of compoupd) pΛ ; Cardioselectivity Example Atria Trachea Kg(Trachea)/K β (Atria) XCI XXXIII 6.1 5.7 2.5 XCII XIII 7.0 7.5 2 XCIII XXXIV 6.4 6.2 2 XCIV IX 6.9 6.6 2 CV XXXV 7.0 6.7 2 CVI XI 6.6 6.0 4 CV11 LX I < 5.5 — XCVIII I 5.9 5.9 CIX II 5.9 ,_ c V inactive 5.0 TABLE V (Cont'd) Test Compound (Numerical designation indicates previous example which describes preparation of compound) pA ; Cardioselectivity Example Atria Trachea K β (Trachea)/K B (Atria) Cl XV 6.6 7.0 -2.5 CII XVI 6.4 6.6 -2 CIII LXV 5.9 Exa oles LXIX-CIII Several of the compounds of the present invention were tested for β- blocking activity in vitro using guinea pig right atria and guinea pig tracheal strips mounted in a tissue bath containing oxygenated (95% 0 2 -5% C0 2 ) Krebs physiological salt solution at 37°C. Each tissue was suspended between a fixed glass rod and a Statha Universal Transducer connected to a Beck an recorder. Atria were allowed to beat spontaneously under a loading tension of approximately 0.5 gm. Instriπsic depressant or stimulant activity was determined for each compound by progressively increasing concentrations in the tissue baths at 50-minute intervals. Tissues were not washed between increments. The maximum concentration showing little or no cardiodepressant activity was chosen for blockade experiments. Changes in rate in response to isoproterenol were measured in the absence and presence of test compounds. Spiral strips of—guinea pig trachea were suspended under 5 gm resting tension and incubated with phentolamine, tropolone and cocaine. Active tension was generated by addition of carbachol (3.0 x 10 " M) a*nd decreases in tension in response to isoproterenol wepe quantitated. Cumulative -concentration-response curves were produced with isoproterenol both before and after 60 minute incubation of test compounds with atria and trachea. The blocking potency of test compounds was estimated by computing pA 2 values (-log Kg) by the method of Furchgott, The Pharmacological Differentiation of Adrenergic Receptors, Ann. N.Y. Acad. Sci., 139: 553-570 (1967). Ccmparision of blockade of right atrial and tracheal responses to i≤oproterenol permitted assessment of cardioselectivity of test compounds; i.e., cardioselective compounds are relatively more effective in blocking atrial rate than tracheal force response to isoproterenol. The degree of cardioselectivity was estimated from the ratio, Kg trachea/Kg atria (10 (pA 2 atria * P A 2 ^achea)^ A ratio greatgr than cne iπdicates cardioselectivity. Test drugs were dissolved in distilled water and added to the bath (30 ml) in a volume of 10 or 100 μl. Thε results of the in vitro tests are contained in Table V. All of the test compounds were active β-blockers. 3_ r e - .^ Examoles CIV - CXXVIII The duration of beta-blockade was determined _i_n vivo using pentobarbital-anesthetized dogs instrumented for measurement of heart rate using a Beck an cardiotachometer triggered electronically by a phasic aortic blood pressure signal. Both vagus nerves " were severed in the cervical region and the animals were mechanically ventilated. Two experimental designs wεre used. The first employed a 40-minute infusion of test compound and the second used a 3-hour infusion of test compound. In the 4C -minute model, isoproterenol was infused into a foreleg vein at the rate of 0.5μg/kg/min to induce a beta-receptor mediated tachycardia. Various doses of test compound where then infused into a femoral vein over a period of 40 minutes. This infusion was then terminated and recovery from blockade was quaπtitated. The percent inhibition of the heart rate response to isoproterenol after 40 minutes of infusion of the test compound was computed along with the total cumulative doses received over the 40-minute period. This cumulative dose is expressed as mg/kg and is an indication of potency. The time period required for 80% recovery of heart rate for each dose of test drug was also measured to quaπtitate duration of action. To facilitate comparison of data between animals, the data for potency and duration of action were normalized to a level of 50% inhibition of the isoproterenol response via least squares regression of data from each animal. Test compounds were dissolved in 0.9% NaCl and infused at a rate of 0.05 ml/kg/min or less. In the 3-hour infusion model, bolus doses.of isoproterenol (0.5μg/kg) were used to assess the degree of beta-blockade and recovery from beta-blockade after termination of the infusion. The doses were spaced at 10-minute intervals and were given before, during and following the infusion of test compounds. The infusion rate was adjusted so that at the end of the 3-hour infusion period the degree of isoproterenol inhibition averaged about 50% of control. The results of the 40-minute infusion are shown in Table VI, and the results of the 3-hour infusion are shown in Table VII. TABLE V I Recovery l imes (mi n. ) Test Compound Example (Numerical designation indicates Potency ( g/kg) 50% 80% 100% Erevious example which es preparation of compound) CIV XV 1.5 10 22 30 0 cv VI 3.4 + 1.1 7 + 2 14 + 3 21 + 3 CVI I 3.5 + 0.5 6 + 1 11 + 1 16 + 2 CVIl V low — — — CVIII ' VIII 1.Θ3-+ .11 7 + 1 14 + 3 20 + 4 CIX X 3.1 + 0.3 11.0 20 + 2 30.0 ex XIII 2.0 + 0.6 7 12 + 1 24 CXI IX 4.7 + 1.7 6 + 1 10 + 1 16 + 2 CXII XI 17.2 + 5.8 8 i 1 16 + 2 25 + 3 CXI11 XII 1.75 19 30 51 CXIV XVIII 1.5 — 0 + 1 Propranolol ~-~- 23 + 4 42 + 0 50 + 9 P Table VII Potency 80% Recovery Time Example Test Compound (mq/kq/100 min) %I* (min) No. of Experiments CXV VI 23.04 63+0 26+8 (4) CXVI VII 21.76 45+2 29+5 (8) • CXV11 XXXIX 3.6jO.6 60+2 17+3 (5) CXVIII XVIII 19.00 46+5 25+ ^ 9 (7) CXIX LIV 1.25 80+4 >60 (3) cxx XXXV 10.7 59 >60 (2) CXXI XV 32.7 54. >60 (2) CXX11 XVII 9.0 03 >60 » (2) CXXIII XXXI 40.7 05 >60 (2) CXXIV XX111 37.6 67+6 >60 (3) Table VI I (Cont 'd) Potency 00% Recovery Time Example ' test Compound (mq/kq/100 min) %I* (min) No. of Experiments CXXV XXXVIII 3.2 , . 6 •7 35, >60 (2) CXXVI L I 4.5 I 79+9 45, >60, >60 (3) . CXXVII XXXVII 12.6 64+5 >60 (4) CXXVIII XXVII 31.0 69 >60 (2) ' Propranolol 0.225 >60 (6) ^Percent inhibition of heart rate response to isoproterenol. Exa ples CXXIX - CXLII These examples describe experiments which demonstrate the dis¬ appearance of the compounds of the present invention in vitro in human whole blood, dog whole blood, and dog liver homogenatε. The rate of disappearance of a compound is expressed as the half-life (T, » 2 ), which is the time period in which one half of the initial amount of compound tested disappears. In each experiment, 1 ml. of a solution containing 50μg of the test compound was addεd to 1 ml. of wholε blood or 1 ml. of a 33% (w/v) liver homogenate. The samples were incubated in a Dubnoff shaking metabolic incubator for 2.5, 5.0, 10.0, 20.0, 30.0 and 60.0 minutes at 37°C. At the designated time periods, the test mixtures were removed from the incubator and transferred to a 0°C ice bath. Acetonitrile (2 ml) was immediately added and the mixtures were mixed to stop enzymatic hydrolysis. Zero time samples_were prepared by adding 2 ml. of acetonitrile to denature the proteins prior to addition of the test compounds. After centrifugation to sediment denatured proteins, 2 ml. of the supernatant was removed and analyzed by high pressure liquid chromatografϋhy, us-ing .a mobile phase of ' 60% acetonitrilε/40% 0.05m sodium phosphate buffer (pH 6.6), a U.V. detector and Waters μ Bondapak Phenyl column. The half life of each test compound was determined graphically by plotting the decrease in concentration as a function of time. The results of the experiments are shown in Table VIII. Table VIM Test Compound (numerical designation indicates previous example which describes preparation of compound) '1/2 (minutes) Example Human Dog Oog Whole Blood Whole Blood Liver Ho ogenate CXXIX XVIII 1.7+0.6 7 — CXXX XII 1.7+0.6 20+15 12+4 CXXXI VI 2.310.6 6.0+2 0.0+3.5 CXXX11 XX 3.5+0.9 4 — CXXXIII X 6+0 67+24 10+4 CXXXIV XIX 0+4 50 — cxxxv XXIII , ' 55+5 150+30 37+20 cxxxvr XVII >>100 »100 147+69 CXXXVII XXXIX 1.4+1 6+2 17+7 cxxxvπi XXXVII 5.3+1 5.5 --._ Table VIII (Cont'd) Test Compound (numerical designation indicates previous example which describes preparation of compound) ' 1/2 (minutes) Example Human Dog Dog Whole Blood Whole Blood Liver Homogenate CXL XXXVIII 6+2 30+2 60+4 CXLI XL 11+5 13 CXLII XLI I » 180 » 180

Claims: CL IMS 1. A method for the treatment or prophylaxis of cardiac disorders in a mammal, comprising administering to such mammal a short- acting β- blocking compound of the formula OH Ar-X-CH-CH 2 -N-R 0 0 0 H 0 0 wherein X is -0-C-, -R-^-O-C-, -O-C-R j -, -R 1 -0-C- 1 -, -C-O-R-,-, or 0 II -R,-C-O-R-,-; R is lower alkyl, lower alkenyl or aralkyl; R^ is lower alkyl; and Ar is unsubstituted aromatic or aromatic substituted with lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halogen, acetamido, amino, nitro, alkylamino, hydroxy, hydroxyalkyl, cyano, or a group of the formula 0 R 2 -0-C-(CH 2 ) n - wherein R 2 is lower alkyl, aryl, or araikyl and n.is an integer from 0 to about 10; or a pharmaceutically acceptable salt thereof. 2. The method of claim 1 wherein R is lower alkyl of from 1 to about 10 carbon atoms, or aralkyl, wherein the alkyl portion contains from 1 to about 5 carbon atoms and the aryl portion contains from 6 to about 10 carbon atoms; R-, is lower alkyl of from 1 to about 5 carbon atoms. 3. The method of claim 1 wherein R is lower alkyl of from 1 to about 5 carbon atoms, or aralkyl, wherein the alkyl portion contains from 1 to about 3 carbon atoms and the aryl portion contains from 6 to about 8 carbon atoms; R-, is methylene; and Ar is unsubstituted phenyl or phenyl substituted with lower alkyl of from 1 to about 5 carbon atoms, fluoro, chloro, nitro, or a group of the formula 0 wherein R« is lower alkyl of from 1 to about 5 carbon atoms and n is an integer from 0 to about 5 ~~ 0 II 4. The method of claim 1 wherein X is -C-O-D-L-; R is selected from the group consisting of isopropyl, t-butyl, and 3,4-dimethoxy- phenethyl; and Ar is unsubstituted phenyl or phenyl substituted with lower alkyl of from 1 to about 5 carbon atoms, fluoro, chloro, or nitro. 5. The method of claim 1 further comprising administering a compound in which R is a group of the formula 0 -Z-C-0-R 2 wherein Z is a straight or branched chain hydrocarbon of from 1 to about 10 carbon atoms, and R 2 is lower alkyl of from 1 to about 5 carbon atoms. 6. The method of claims 1, 2, 3, 4 or 5 wherein the compound is administered parenterally. 7. " The method of claim 6 wherein the compound is administered by intravenous injection or intravenous infusion at a dosage rate of from about 0.001 to about 100 mg. of compound per kg. of . body weight of said mammal per hour. 8. The method of claim 5 wherein the compound is administered by intravenous injection o intravenous infusion at a dosage rate of from about 0.01 to about 10 mg. of compound per kg. of body weight of said mammal per hour. 9. A compound of the formula OH Ar-X-CH-CH 2 -N-R 0 0 0 H 0 wherein ^ X is -0-C-, -R,-0-C«, -0-C-R,-, or -R,-0-C-R,-; R is lower alkyl, or aralkyl; R-, is lower alkyl; and Ar is unsubstituted aromatic or aromatic substituted with lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halogen, aceta idoj amino, nitro, alkylamino, hydroxy, hydroxyalkyl, cyano, or a " group of the formula 0 R 2 -0-C-(CH 2 ) n - wherein R 2 is lower alkyl, aryl, or arakyl and n is an integer from 0 to about 10; or a pharmaceutically acceptable salt thereof. 10. The compound of claim 9, wherein R is lower alkyl of from 1 to about 10 carbon atoms, or aralkyl, wherein the alkyl portion contains from 1 to about 5 carbon atoms and the aryl portion contains from 6 to about 10 carbon atoms; R-. is lower alkyl of from 1 to about 5 carbon atoms. 11. The compound of claim 9, wherein R is lower alkyl of from 1 to about 5 carbon atoms, or aralkyl, wherein the alkyl portion contains from 1 to about 3 carbon atoms and the aryl portion contains from δ to about 8 carbon atoms; R-, is methylene; and Ar is unsubstituted phenyl or phenyl substituted with lower alkyl of• from 1 to about 5 carbon atoms, f.luoro, chloro, nitrcf, or a.group of the formula 0 R 2 -0-C-(CH 2 ) n - wherein R 2 is lower alkyl of from 1 to about 5 carbon atoms and n is an integer from 0 to about 5. 0 II 12. The compound of claim 9 wherein X is 0-C-; R is selected from the group consisting of isopropyl, t-butyl, and 3,4-dimethoxy- phenethyl; and Ar is unsubstituted phenyl or phenyl substituted with lower alkyl of from 1 to about 5 carbon atoms, fluoro, chloro, or nitro. 13. The compound of claim 9 in which R is a group of the formula 0 Z-C-0-R 2 - wherein Z is a straight or branchεd chain hydrocarbon from 1 to about 10 carbon atoms, and R 2 is lower alkyl from 1 to about 5 carbon atoms. 14. A compound of the formula wherein R is isopropyl or t-butyl, or a pharmaceutically acceptable salt thereof. 15. A compound of the formula wherein R is isopropyl, t-butyl, or 3,4-dimethoxyphenethyl, or a pharmaceutically acceptable salt thereof. 16. A compound of the formula wherein R is isopropyl or t-butyl, or a pharmaceutically acceptable salt thereof. 17. A compound of the formula wherein R is. isopropyl or t-butyl, or a pharmaceutically acceptable salt thereof. 18. A compound of the formula ' wherein R is isopropyl or t-butyl, or a pharmaceutically acceptable salt thereof. 19. A compound of the formula wherein R is isopropyl or t-butyl, or a pharmaceutically acceptable salt thereof. 5'w • • « z- A ~ f 20. A process for preparing a compound of the formula OH Ar-X-CH-CH -N-R ά H 0 0 tl II wherein X is -0-C- or -0-C-R,; R is lower alkyl, lower alkenyl, or aralkyl; R-e is lower alkylene; and Ar is unsubstituted aromatic or aromatic substituted with lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halogen, aceta ido, amino, nitro, alka ino, hydroxy, hydroxyalkyl, cyano, or a group of the formula R 2 -0-C-(CH 2 ) n - wherein. R^.is lower alkyl, aryl, or aralkyl and n is an integer from 0 to about 10; or. a pharmaceutically acceptable salt thereof, which com¬ prises reacting a compound of the formula Ar OH, wherein Ar .is defined as hereinbefore, with a compound of the formula OH H-X-CH-CH--N-R L H wherein X and R are defined as herεinbeforε and thε hydroxyl and amino groups have been protected with suitable protecting groups, followed by cleavage of the protective groups to give the final product which may optionally be converted to a pharmaceutically acceptable salt by reaction with an appropriate acid. 21. A process for preparing a compound of the formula OH Ar-X-CH-CH~-N-R c H wherein X is -R- j -O-C- or -R-.-0-C-R-^-; R is lower alkyl, lower alkenyl, or aralkyl; R, is lower alkylene; and Ar is unsubstituted aromatic or aromatic substituted with lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halogen, acetamido, amino, nitro, alkamino, hydroxy, hydroxyalkyl, cyano, or a group of thε formula R 2 -0-C-(CH 2 ) n - wherein R 2 is lower alkyl, aryl, or aralkyl and n is an integεr from 0 to about 10; or a pharmaceut cally acceptable salt thereof, which com¬ prises reacting a compound of the formula Ar-R,-0H, wherein Ar and R-, are defined as hereinbefore, with a compound of the formula 0 OH H0-C-R,-CH-N-R 1 H wherein R, is * lower alky ene or a direct bond, by heating thε reactaπts to reflux in a suitable solvent such as benzene which has been made acidic to help catalyze the reaction to give the final product which may optionally be converted to a pharmaceut cally acceptable salt by reaction with an appropriate acid. • 22. — A process for preparing a compound of the formula OH Ar-X-CH-CH~-N-R H - 0 0 wherεin X is -C-O-R j - or -R- j -C-0-R. j -; R is lowεr alkyl, lower alkenyl, or aralkyl; R, is lower alkyl ene; and Ar is unsubstituted aromatic or aromatic substituted with lower alkyl, lower alkenyl, Tower alkynyl, lower alkoxy, halogen, acetamido, amino, nitro, alkamino, hydroxy, hydroxyal yl , or cyano; or a pharmaceutically acceptable salt thereof, which comprises: a) reacting a compound of the formula Ar-X-C AH-O-L wherein Ar and X are defined as hereinbefore with a compound of the formula H 2 N-R, wherein R is defined as hereinbefore, by heating the reactaπts to reflux to give the final product which may optionally be converted to a pharmaceutically acceptable salt by reaction with an appropriate acid; or OH I b) reacting a compound of the formula H0-R,-CH-CH 2 -NH-R, wherεin R and R, are defined as hereinbefore, with an acyl chloride of the 1 0 II formula Ar-R,-C-Cl, wherein R, is lower alkylene or a direct bond, in a suitable solvent to give the product which may optionally be converted to a pharmaceutically acceptable salt by reaction with an appropriate acid. 23. The process of claim 20, 21 or 22 for producing a compound OH " I of the formula Ar-X-CH-CH 2 -NH-R wherein X is defined as before and R is lower alkyl of from 1 to about 10 carbon atoms, or aralkyl, wherein the . . . • . . » alkyl portion contains from 1 to about 5 carbon atoms and the aryl . portion contains from 6 to about 10 carbon atoms; R«. is lower alkylene of from 1 to about 5 carbon atoms. 24. The process of claim 20, 21 or 22 for producing a compound OH - I of the formula Ar-X-CH-CH 2 -NH-R wherein X is defined as before and R is lower alkyl of from 1 to about 5 carbon atoms, or aralkyl, wherein the alkyl portion contains from 1 to about 3 carbon atoms and the aryl portion contains from 6 to about 8 carbon atoms; R, is methylene; and Ar is unsubstituted phenyl or phεπyl substituted with lower alkyl of from 1 to about 5 carbon atoms, fluoro, chloro, nitro, or a group of the formula - _ 0 _ R 2 -0-C-(CH 2 ) n - wherein R? is lower al yl of from 1 to about 5 carbon atoms and n is an integer from 0 to about 5. — 25. The process of claim 20- for producing a compound of the OH 0 formula Ar-X-CH-CH 2 -NH-R wherein X is -0-C-; R is selected from the group consisting of isopropyl, t-butyl, and 3,4-dimethoxyphenethyl; and Ar is unsubstituted phenyl or phenyl substituted with lower alkyl of from 1 to about 5 carbon atoms, fluoro, chloro, or nitro. 26. The process of claim 20, 21 or 22 for producing a compound OH of the formula Ar-X-CH-CH 2 -N-R, wherein X άnd Ar are defined as before and R is a group of the formula Z-C-0-R 2 - wherein Z is a straight or branched chain hydrocarbon from 1 to about 10 carbon atoms, and R~ is lower alkylene from 1 to about 5 carbon atoms. 27. A process according to claim 22 for producing a compound of . the formula wherein R is isopropyl or t-butyl , or a pharmaceuti cal ly acceptable salt thereof. 28. A process according to cl aim 22 for producing a compound of the formul a wherein R is isopropyl, t-butyl, or 3,4-dimethoxypheπethyl, or a pharmaceutically acceptable salt thereof. 29. A process according to claim 22 for producing a compound of the formula wherein R is isopropyl or t-butyl, or a pharmaceutically acceptable salt thereof. 30. A process according to claim 22 for producing a compound of the formul wherein R is isopropyl or t-butyl, or a pharmaceutically acceptable salt thereof.— 31. A process according to claim 22 for producing a compound of the formula wherein R is isopropyl or • t-butyl, -or a pharmaceutically acceptable salt thereof. 32. A process according to claim 22 for producing a compound of the formula wherein R is isopropyl or t-butyl, or a pharmaceutically acceptable salt thereof.

Inventors: BORGMAN ROBERT J, ERHARDT PAUL W, KAM SHEUNG TSAM, O DONNELL JOHN P
Applicants: AMERICAN HOSPITAL SUPPLY CORP
Application year: 1981
Main classification: C07C101
IPC codes: C07C67, C07C213, C07C219, C07C227, C07C229, C07C231, C07C233, C07C253, C07D213, C07D309