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 R may be lower alkyl, aryl, or aralkyl; n may be an integer from 0 to about 10; x may be an integer from 1 to 3; Ar may be substituted or unsubstituted aromatic; R<u1>u may be lower alkyl, or aralkyl; and pharmaceutically accepted salts thereof. Novel compounds possessing short acting ss-adrenergic blocking activity are also disclosed.

Description: METHOD FOR TREATMENT OR PROPHYLAXIS OF CARDIAC DISORDERS Background 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 3-adreπergic blocking agents and to compounds useful n such method. The therapeutic and prophylactic uses of compounds which block sympathetic nervous stimulation of β-adrenergic receptors in the heart, 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 preven¬ tion of further tissue damage and can relieve angina pectoris. 3-Adrenergic stimulation may also aggravate or cause arrhythmias because of increased levels of catechol amines. Thus (3-blocking agents may be employed to reduce the risks of arrhythmias. Compounds have been discovered which selectively block 3-adrenergic receptors in various organs. Beta receptors in the heart are generally referred to as ^ receptors, and those associated with vasodilation and bronchodilation are $2 receptors. Selective β-blockers are preferred for the treatment of cardiac disorders, because they may have less potential to cause hypertension ' or bronchoconstriction. A number of β, sel ective adrenergic blocki ng agents have been discovered. Smith, L. H. , J. Appl . Chem. Biotechπol . , 28, 201-212 (1978) . Most of such compounds are structural vari ations of l-am no-3-aryloxy-2-propanol . Heretofore, the emphasis in β-blocker research has been to develop compounds whi ch can be admi nistered to cardiac patients over long periods of time. However, often it is desirable in the critical care setti ng to quickly reduce heart work or improve rhythmicity during a cardi ac crisis , e.g. , duri ng or shortly after a myocardi al infarc¬ tion. Conventional β-blocking agents can be employed for such treat¬ ment, but their duration of action may be much l onger than des ired by the physician. A β-blαcking agent possessing a long duration of action does not all ow 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 des irable to quickly reduce or el iminate β-blocki ng activity. The lingering activity of avai lable β-blocking agents can be counterproductive and can greatly complicate the therapeutic decisions required of the physici an duri ng such critical care of cardi ac patients. Accordingly, there is a need for a pharmaceutical preparation and method of treatment, employi ng a β-adrenergic 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 of prophylaxis of cardiac disorders in a mammal comprising administering to such mammal a short acting compound of the formula: OH ROC - (CH 2 ) n - Ar-0-CH 2 -CH-CH 2 -NH-R 1 wherein R is lower alkyl , lower cycloalkyl , lower alkenyl , lower alkyl or aryl carboxy ethyl , lower hal oal kyl , aral kyl or aryl ; n is an i nteger from 0 to about 10; x is an integer from 1 to 3, provided that when x is 0 II greater than 1, different occurances of the R-0-C-(CH 2 ) n - group may be the same or different; Ar is unsubstituted aromatic or aromatic substi¬ tuted with lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halogen, acetamido, amiπo, nitro, lower alkyla ino, hydroxy, lower hydroxyalkyl or cyano; R^ is lower alkyl, or aralkyl; or a pharmaceuti¬ cally acceptable sale thereof. Detailed Description of the Invention Compounds administered by the method of the present invention are represented by the formula: OH ROC - (CH 2 )- Ar-0-CH 2 -CH-CH 2 -NH-R ] wherein R represents lower alkyl of straight or branched carbon chains from 1 to about 10 carbon atoms, lower cycloalkyl of from 1 to about 5 carbon.atoms, lower alkenyl of from 2 to about 5 carbon atoms, lower alkynyl of from 2 to about 5 carbon atoms, lower alkyl carboxymethyl in which the alkyl portion contains from 1 to about 5 carbon atoms, aryl carboxymethyl in which the aryl portion contains from 6 to about 8 carbon atoms, lower haloalkyl of from 1 to about 5 carbon atoms, aryl of from 6 to about 10 carbon atoms or aralkyl wherein the alkyl portion contains from about 1 to about 5 carbon atoms and the aryl portion represents substituted or unsubstituted monocyclic or polycyclic aroma¬ tic or heterocyclic ring systems of from 6 to about 10 carbon atoms; n represents an integer from 0 to about 10; x represents an integer from 1 to 3, provided that when x is greater than 1, different occurances of 0 II the R-0-C(CH 2 ) n group may be the same or different; Ar represents sub¬ stituted or unsubstituted aromatic, including monocyclic, polycyclic and heterocyclic ring systems, wherein aromatic substituents include lower alkyl of from 1 to about 10 carbon atoms, lower alkenyl or from 2 to about 10 carbon atoms, lower alkynyl of from 2 to about 10 carbon atoms, lower alkoxy of from 1 to about 10 carbon atoms, halogen, acetamido, amino, nitro, lower a!kyl mino, of from 1 to about 10 carbon atoms, hydroxy, lower hydroxy alkyl of from 1 to about 10 carbon atoms, and cyano; R^ represents lower alkyl of from 1 to about 10 carbon atoms, such as methyl, propyl, hexyl, isopropyl, and the like; 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, such as benzyl, phenethyl, naphthyl ethyl, 3,4-dimethoxyphenethyl and the like. Such compounds may be administered as their pharmaceutically acceptable acid addition salts, e.g., as the hydrochloride, sulfate, phosphate, gluconate, tartrate, etc. In preferred compounds, n is an integer from 0 to about 5, and x is 1 or 2, and in particularly preferred compounds, Ar is phenyl, x is 1 or 2 and n is an integer from 0 to about 3. It has been found that the compounds in which Ar is phenyl and para-substituted, β-blocking potency and shortness of duration of action are improved when n is at least 1, i.e. the ester group is isolated from the aromatic ring by at least one ethylene unit. Alternatively, in compounds in which Ar is 0 II phenyl, at least one of the ester-conta ning groups, R-0-C-, is advantageously in the ortho-position with respect to the side chain. It is surprising and presently unexplained, that two configurations of the compounds of the present invention, para-substitution with an ester carbonyl isolated from the aromatic ring and ortho-substitution with the ester carbonyl attached directly to the aromatic ring, provide enhanced β-blocking potency and relatively short duration of action. In preferred compounds, the ester substituent, R, is lower alkyl of from 1 to about 5 carbon atoms, such as methyl, ethyl, π-butyl, n-pentyl, and the like; lower alkenyl of from 2 to about 5 carbon atoms, such as ethyl, 2-propenyl, 2-methyl-3-butenyl and the like, or lower cycloalkyl of from 3 to about 5 carbon atoms such as cyclopropyl, cyclopentyl, 2-me thy 1 cyclopropyl, and the like; R^ is lower alkyl of from 1 to about 5 carbon atoms such as methyl, ethyl, propyl, t-butyl, pentyl and the like, or aralkyl, wherein the alkyl portion contains from 1 to about 5 carbon atoms and the aryl portion contains from 5 to about 10 carbon atoms, such as benzyl, phenethyl, dimethoxyphenethyl, naphthyl ethyl, phenyl butyl, and the like. Aromatic substituents include lower alkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, lower - _.E_ alkoxy of from 1 to about 5 carbon atoms, halogen, acetamido, amino, nitro, lower alkylamino of from 1 to about 5 carbon atoms, hydroxy, lower hydroxyalkyl of from 1 to about 5 carbon atoms, and cyano. Preferred aromatic substituents are lower alkyl of from 1 to about 5 carbon atoms, fluoro, chloro, and alkyl. The compounds descri bed herei n may be prepared by any suitable procedure . The compounds are advantageous ly prepared by reacti ng an appropriate phenol derivative with epichl orohydri n i n the presence of a base to form a l,2-epoxy-3-aryl oxypropane derivative accordi ng to the fol lowi ng reaction: ROC - (CH 2 ) Ar-OH + C1-CH 2 -CH-CH 2 base ROC - Ar-0-CH 2 -CH-CH 2 wherein Ar, R, n, and x are defined as above. The l, 2-epoxy-3-aryloxy- propane so prepared may then be reacted with an amine to form the desi red product: This reaction is preferably conducted in an alcoholic solvent identical to the ester adduct to prevent alcoholysis side reactions, e.g. when R is methyl, the reaction solvent is preferably methanol. The phenol derivatives used as starting materials in the reaction scheme described above are generally commercially available compounds or may be prepared by methods known in the art. For instance, for the preparation of some preferred compounds of the * present invention, suit¬ able starting materials include methyl 2-hydroxybeπzoate, methyl (4- hydroxyphenyl) acetate, methyl 4-hydroxypheπyl propionate, and the like. 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 short 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 metabolic 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 XXXVI-LI. The compounds have been found to be generally non- toxic within conventional dosage ranges. Dosages of 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 present i nvention is further i llustrated by the fol lowi ng examples which are not intended to be limiting. EXAMPLE I This example describes the experimental procedure for producing the following compound: OH Ch 3 0-C Methyl 4-(2,3-Epoxypropoxy)benzoate A mixture of 15.2 gm (0.1 mole) of methyl 4-hydroxybenzoate, 27.6 gm (0.2 mole) potassium carbonate and 31 mL(0.4 mole) epichlorohydrin in 250 L acetone was heated to reflux for 24 hours. The reaction medium was then filtered and evaporated. The residue was taken up in 100 L toluene and washed with 100 mL 1.0 N NaOH and 2xl00mLwater. The toluene phase was then dried over magnesium sulfate and evaporated to provide the crude product as an oil.. Purification was effected by vacuum distillation (66-67°; 75 u pressure) and provided 14 gm (67%) of a clear oil when gradually crystallized at room temperature: mp 54-55°C. The Nf*R and IR spectra and elemental analysis data were consistent with the assigned structure. Methyl 4-[2-Hydroxy 3-(isopropylamino)propoxy] benzoate Hydrochloride A mixture of 2.1 gm (0.01 mole) of the epoxide derivative described above and 0.9 mL (0.01 mole) * of isopropyl mine in 25 L of methanol was heated to reflux for 2 hours. The reaction medium was evaporated to a clear oil which was then taken up in methanol and treated with ethereal HC1. Crystals formed at room temperature and provided 1.25 gm (41%) of product having a melting point of 168-169°C. The NM* spectrum was consistent with the assigned structure and the elemental analysis was consistent with the molecular formula C^H^Cl N0 4 . EXAMPLE II This example describes the experimental procedure for producing the following compound: OH Ethyl 4-(2,3-Epoxypropoxy)beπzoate A mixture of 16.7 gm (0.10 mole) of ethyl 4-hydroxybenzoate, 20.7 gm (0.15 mole) of potassium carbonate and 24 mL (0.30 mole) of epichlorohydrin in 250 L acetone was heated to reflux for 12 hours. The reaction medium was then filtered and evaporated. The resulting oil was taken up in 100 L toluene and washed with 100 mL 1.0 N sodium hydroxide and 2x100 mL water. The toluene phase was then dried over magnesium sulfate and evaporated to give 13.5 gm (61%) of a clear oil. The NNR spectrum of this oil was consistent with the assigned structure and the oil was used in the next reaction step without further purifica¬ tion. Ethyl 4-[2-Hydroxy-3-(isopropylaπnno)propoxy]benzoate Hydrochloride A mixture of 2.2 gm (0.01 mole) of the epoxide derivative prepared as described above and 25 L (0.28 mole) of isopropylam ne in 25 mL of ethanol was heated to reflux for 2 hours. The reaction medium was then evaporated to a clear oil which was dissolved in ethanol and treated with ethereal HC1. The white crystals which were produced (1.07 gm, 35%) had a melting point of 112-114°C. The NJ-R spectrum was consistent with the assigned structure and the elemental analysis was consistent with the molecular formula C, c H 24 Cl 0 4 . EXAMPLE III This example describes the experimental procedure for producing the following compound: OH 0CH 2 -CH-CH 2 - H-CH(CH 3 ) 2 . HC1 Methyl (4-Hydroxyphenyl ) acetate A solution of 15 gm (0.1 mole) of 4-hydroxyphenyl cetic acid in 500 mL methanol and 2 mL concentrated sulfuric acid was placed in a Soxhlet extractor charged with 3A molecular sieves. The solution was heated to reflux for 72 hours, and the sieves were exchanged at 24-hour intervals. The reaction medium was then evaporated to an o l which was dissolved in 100 L toluene and extracted with 3x100 L water. The toluene phase was dried over magnesium sulfate, treated with activated charcoal and evaporated to provide 13 gm (80% yield) of a yellow oil. The NMR spectrum was consistent with the assigned structure and this material was used in the next reaction step. Methyl 4-(2,3-Epoxypropox.y)phenyl acetate The oil described in the preceding reaction was utilized directly i.n the condensation reaction with epichlorohydrin, potassium carbonate and acetone as described in Example I to provide the desired aryl ether epoxide in 60% yield. The NR spectrum of the clear oil obtained in this manner was consistent with the assigned structure. Methyl 4-[2-Hydroxy-3-(isopropylamino)propoxy] phenyl acetate hydrochloride A mixture of 2.2 gm (0.01 mole) of methyl 4-(2,3-Epoxypropoxy)- phenylacetate and 1.7 mL (0.02 mole) of isopropyl mine in 25 mL methanol was heated to reflux for 2.5 hours. The reaction medium was then evaporated, and the resulting oil was dissolved in methanol and treated with ethereal HC1 to provide 0.6 g (19%) of white crystals: mp 119-121°. The NR spectrum was consistent with the assigned structure and the elemental analysis was consistent with the molecular formula C 15 H 24 N0 4 C1. EXAMPLE IV This example describes the experimental procedure for producing the following compound: OH 2 Methyl 3-(4-Hydrox,yphenyl ) propionate A solution of 17 gm (0.1 mole) of 3-(4-hydroxypheπyl) propionic acid in 500 mL methanol and 2 mL concentrated sulfuric acid was placed in a Soxhlet extractor charged with 3A molecular sieves. The solution was refluxed for 72 hours and the sieves were exchanged at 24 hour intervals. The reaction medium was then evaporated to an oil which was dissolved in 100 L toluene and extracted with 3x100 mL water. The toluene phase was dried over magnesium sulfate, treated with activated charcoal and evaporated to provide 15 gm (80%) of a clear oil. The NMR spectrum was consistent with the assigned structure and this material was utilized directly in the next reaction step. Methyl 3-[4-(2,3-£poxypropoxy)phenyl] propionate The oil described above was utilized directly in the condensation reaction with the epichlorohydrin, potassium carbonate, and acetone as described in Example I. Purification was effected by vacuum distilla¬ tion (156°; 0.4 mm pressure) and provided the aryl ether epoxide in 45% yield. The Hb%\ spectrum of the clear oil obtained by this procedure was consistent with the assigned structure and the elemental analysis was consistent with the molecular formul C^H^gO^Cl. Methyl 3-[4-[2-Hydrox.y-3-(isopropylamino)propoxy] phenyl] propionate Hydrochloride A mixture of 50 gm (0.21 mole) of methyl 3-[4-(2,3-epoxyproxy)- phenyl] propionate and 100 mL of i so propyl ami ne in 100 mL methanol was heated to reflux for 4 hours. The reaction medium was then evaporated and the resulting oil taken up in methanol and treated with ethereal HC1 and provided crystals which were recrystallized in similar fashion to provide 28 gm (47%) of white crystals: mp 85-86°. The NW. and IR spectra and the elemental analysis data were consistent with the assigned structure having a molecular formula of C,gH 2 gN0.Cl. L -7 P EXAMPLES V - VII These examples describe procedures for preparing the compounds identified in Table I. The procedure of Example IV was repeated in all essential details, except the amine reactant listed in Table I was substitued for isopropylamine. The NMR and IR spectra and elemental analyses of each of the compounds so prepared conformed to the assigned structure. TABLE I Amine Mel ti ng Example Reactant R j -WU -1 Poi nt V t-butyl ami ne t-butyl 144-146°C VI • 3,4-dimethoxyphen- 3,4-dimethoxy- 138-140°C ethyl amine phenethyl VII benzyl ami ne benzyl 180-181°C EXAMPLE : VI II This example describes experimental procedures for preparing the following compound: OH 0-CH 2 -CH-CH 2 -NH-C(CH 3 ) 3 CH 3 0-C Methyl 4- [ 2-H yd rox.y-3-( t-butyl a i no) pro poxy] benzoate A mi xture of methyl 4-(2, 3-epoxypropoxy) benzoate (prepared as descri bed i n Exampl e I) (2.1g, 0.01 mol e) , 10 L of t-butyl amine and 10 mL of methanol was heated to reflux for three hours. The reaction medi um was then evaporated under reduced pressure to provi de the amine as an oi l . The free ami ne was crystal li zed from hexane-ethyl acetate i n 65% yield: m.p. 88-89°C. The NNR spectrum and elemental analysis were consistent with the assigned structure. EXAMPLES IX. X AND XI These examples describe the preparation of the following compounds: Example IX OH 0-CH 2 -CH-CH 2 -NH-CH(CH 3 ) 2 Example X OH 0-CH 2 -CH-CH 2 -NH-C(CH 3 ) 3 Example XI Methyl 2-(2,3-Epoxypropoxy)benzoate * A mixture of 15.2 g (0.10 mole) of methyl 2-hydroxybenzoatε, 27.6 g (0.20 mole) of Ko^S and 3 **" ml " ^-^ mole ) °f epichlorohydr n in 250 L of acetone was heated to reflux for 24 hours. The reaction medium was then filtered and evaporated under reduced pressure. The resulting oil was dissolved in 100 mL toluene and washed consecutively with 100 mL water, 2x100 L 1.0 N NaOH, and 2x100 L water. The organic phase was then dried over MgSO, and evaporated under reduced pressure to provide the crude product as an oil. Purification was effected by vacuum distillation to provide an oil in 12% yield: boiling point 148°C (75u). The NMR and IR spectra and elemental analysis were consistent with the assigned structure. Methyl 2-[2-Hydrox,y-3-(isopropy1 ami no)propoxy] benzoate (Example IX) A mixture of 2.1 g (0.01 mole) of methyl 2-(2,3-epoxypropoxy) benzoate, 100 mL of isopropylamine and 10 mL of methanol was heated to reflux for three hours. The reaction medium was then evaporated under reduced pressure to provide the amine as an oil. The oil was treated with hexane: ethyl acetate (9:1) to generate the free amine as a crystalline product in 63% yield: m.p. 78-79°C. The NNR spectrum and elemental analysis were consistent with the assigned structure. Methyl 2-[2-H,ydroxy-3-(t-but.yl ami no )propoxy] benzoate Hydrochloride He i hydrate (Example X) This material was prepared by the same reaction used for the compound of Example IX except that t-butyl amine was substituted for isopropylamine and the crystalline hydrochloride salt was prepared in 30% yield by adding aqueous HCl to a methanolic solution followed by trituration with ether: m.p. 116-118°C. The Nf-R spectrum and elemental analysis were consistent with the assigned structure. Methyl 2-[2-Hydroxy-3-(3,4-dimethox.yphenethylamino)prQpoxy] benzoate Oxalate (Example XI) This material was prepared by the same reaction used for the compound of Example IX except that 3,4-dimethoxyphenethyl δπrine was sub¬ stituted for isopropylamine, and the product was crystallized as its oxalate salt from methanol -ether in 25% yield: m.p.125-126°C. The NMR spectrum and elemental analysis were consistent with the assigned- structure. EXAf-PLE XII This example describes procedures for producing a compound of the for ula CH- j -CH 2 -CH 2 -0- -CH 2 -NH-CH(CH 3 ). π-Propyl 3-(4-Hydroxypheπyl ) propionate A sol ution of 15 g (.09 mol e) of 3-(4-hydroxyphenyl )propionic acid in 250 mL of n-propanol containing 5 drops of cone. H 2 S0 4 was heated to reflux for 72 hr in a Soxhlet Extractor charged with 50 g of 3A molecular sieves. The reaction medium was then evaporated under reduced pressure and the resulting oi l dissol ved i n 100 L toluene and washed with three 50 mL portions of water. The toluene phase was then dried with MgSO, and evaporated under reduced pressure to provi de 12 g (64%) of a clear oi l which was uti lized directly i n the next step without additional purification. The NM* spectrum was consistent with the assigned structure. n-Propyl 3-[4-(2-,3-Epoxypropoxy)pheπyl] propionate A mixture of 9 g (0.04 mole) of n-propyl 3-(4-hydroxyphenyl ) propionate, . 10 g (0.08 mol e) of K 2 C0 3 and 12 mL (0.15 mol e) of epichlorohydrin in 150 L of acetone was stirred and heated to reflux for 20 hours. The reaction medi um was then fi ltered and evaporated under reduced pressure. The resulting oi l was taken up in 100 mL toluene and washed consecutively with 50 mL water 2x50 mL of 1 N NaOH and 2x50 mL of water. The toluene phase was then dried over MgSQ * and evaporated under reduced pressure to provide 3 g (30%) of a cl ear oi l which was used directly in the next step without additional purifica¬ tion. The IR and NMR spectra of the reaction product were consistent with the assigned structure. n-Prop . yl 3-[4-[2-H.ydrox.y-3-(isopropylamino)propoxy]phenyl] propionate Hydrochloride A solution of 1.5 g (0.006 mole) of n-propyl 3-[4-(2,3-epoxy- propoxy) phenyl] propionate in 10 mL of isopropyl mine and 20 L of n- propanol was heated to reflux for 4 hours. The reaction medium was then evaporated under reduced pressure to provide the crude free amine as an oil. The oil was dissolved in n-propaπol and treated with ethereal HCl and provided 1.2 g (56%) of white crystals: mp 88-92°C. The NMR spectrum of the product was consistent with the assigned structure and the elemental analysis data was consistent with the molecular formula C 18 H 30 N0 4 C1. EXAMPLE XIII The experiment of Example IV was repeated in all essential details to produce a compound of the formula OH except that 3-( -hydroxyphenyl )propionic acid was substituted for 3-(4- hydroxyphenyl ) propionic acid, and the final product was crystal li zed as its oxal ate sal t from methanol -ether. The product melted at 92-94°C and NMR spectrum and elemental analys is were consistent with the assigned structure . EXAMPLE XIV This exampl e describes procedures for producing a compound of the formul a 3-Propenyl 4-H.ydroxybenzoate A mixture of 27.6 g (0.2 mole) of 4-hydroxybenzoic acid, 13.8 g (0.1 mole) of K 2 C0 3 and 24 g (0.2 mole) of ally! bromide in 350 L of acetone: H 2 0 (9:1) was heated to reflux for 3 hours. The acetone l ayer was separated and evaporated to dryπess jn , vacuo and the residue was recrystal li zed from CC1 4 to give 19.7 g (55%) of white crystals: p 92- 96°, whose NNR spectrum was cons istent with the assigned structure. 3-Propenyl 4-(2,3-Epoxypropoxy) benzoate The experimental procedure of Example I for preparing Methyl 4- (2, 3-epoxypropoxy) benzoate was repeated in al l essential detai ls, except 3-propenyl 4-hydroxybeπzoate was substituted for methyl 4- hydroxy benzoate. The reaction yielded a clear oi l in 61% yield, whose NM* spectrum conformed with the assigned structure. 3-Propenyl 4-[2-Hydroxy-3-( sopropyl amino) propoxy] benzoate The experimental procedure of Example I .for preparing methyl 4- [2-hydroxy-3-(isopropyl amino)propoxy] benzoate hydrochloride was re¬ peated in all essenti al detai ls, except 3-propεnyl 4 -2,3 (epoxy propoxy )- benzoate was substituted for methyl 4-(2,3-epoxypropoxy) benzoate. Al ly! alcohol was employed as the reaction solvent, and the reaction product was crystal li zed as the free amine from hexane: ethyl acetate (4:1) in approximately 25% yield. The product melted at 63-64°C and its Nf*R spectrum and elemental analysis conformed to the assigned struc- ture. EXAMPLES XV AND XVI The procedures of Example XIV were repeated i n al l essential details to produce the compounds identified i n Table II, except that 3- hydroxybenzoic acid was substituted for 4-hydroxybenzoic acid as the starti ng material i n Example XV and 2-hydroxybenzoic acid was substituted for 4-hydroxybenzoic acid- as the starting materi al in Example XVI. Both compounds were crystal lized as their oxal ate salts. The NMR spectra and elemental analyses of the compounds were consistent with tjie assigned structures . TABLE II Example Compound Melting Point OH C-0-CH 2 -CH=CH 2 .(COOH) 2 EXAMPLES XVII - XXXII Several of the compounds of the present invention were tested for β-blocking activity n vitro using guinea pig right atria and guinea pig trachea! 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 Statham Universal Transducer connected to a Beckman recorder. Atria were allowed to beat spon¬ taneously under a loading tension of approximately 0.5g. Changes in rate of response to isoproterenol , a standard β-receptor agonist, were measured in the absence and presence of test compounds. Spiral strips of guinea pig trachea were suspended under 5g resting tension and incubated with phentol amine, tropolone, and cocaine. Active tension was generated by addition of carbachol (3.0 x 10 " M) and decreases in tension in response to isopoterenol were quantitated. Cumulative con¬ centration response curves were produced with isoproterenol both before and after 60-minute incubation of test compounds with atria and trachea. Compounds with β-blocking activity shifted concentration response curves to the right. The blocking potency of test compounds was estimated by computing pA 2 values (-log g) by the method of Furchgott (The Pharmacological Differentiation of Adrenergic Receptors., Ann. N.Y. Acad. Sci. 139:553-570, 1967). Comparison of blockade of right atrial and trachea! response to isoproterenol permits assessment of cardioselectivity of test compounds; i.e., cardio- selective compounds are relatively more effective in blocking atrial rate than trachea! force responses to isoproterenol. The degree of cardioselectivity was estimated from ratio K g trachea/Kg atria 10^ p ^ Atria -pA 2 Trachea). A ratio greatsr than one indicates cardio- selectivity. The results obtained with several of the test compounds are con¬ tained in Table III. All of the compounds are β-blockers. TABLE III Test Compound (Numerical Designation Indicates Previous Example Which Describes pA-. Preparation of Cardio¬ Example Compound) Atria rrachea selectivity XVII IV 7.0 5.6 30 XVIII V 6.5 5.9 4 XIX VI 6.5 5.2 20 XX VII 5.9 4.9 10 XXI XII 5.4 5.2 1.6 XXII XIII 8.6 8.9 0.5 XXIII III 6.4 5.4 10 XXIV XIV 6.3 5.7 4 XXV XV 6.9 7.2 2 XXVI XVI .7.9 7.9 * 1 XXVII IX 8.2 7.9 2 XXVIII I 6.8 5.5 19 XXIX II 6.5 6.1 2.5 XXX X 8.8 8.9 1 XXXI VIII 6.5 5.4 32 XXXII XI 8.3 7.1 16 Propranolol 8.7 8.9 0.7 Practolol 6.6 5.8 6 EXAMPLE XXXIII The duration of beta-blockade was determined i n vivo using pento- barbital -anesthet zed dogs i nstrumented for measurement of heart rate using a Beck an cardiotacho eter triggered electronically by a phasic aortic blood pressure signal . Both vagus nerves were severed i n the cervical region and the animals were mechanically ventilated. Two experimental designs were used. The first employed a 40 -minute i nfusion of test compound and the second used a 3-hour i nfusion of test compound. In the 40-minute model , isoproterenol was i nfused into a foreleg vein at the rate of 0.5mg/kg/min to induce a beta-receptor mediated tachcardi . Various doses of test compound were then infused into a femoral vein over a period of 40 minutes. This i nfusion was then termi nated and recovery from blockade was quantitated. The percent Inhibition of the heart rate response to isoproterenol after 40 minutes df infusion of the test compound was computed al ong with the total cumulative doses received over the 40-minute period. This cumulative dose is expressed as g/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 quantitate duration of action. Potency and duration of action were normali zed to a level of 50% inhibition of the isoproterenol response via least squares regression of data from each animal. Test compound were dissolved in 0.9% NaCl and i nfused at a rate of 0.05 ml/kg/min or less . In the 3-hour infusion model , bol us doses of isoproterenol (0.5gm kg) were used to assess the degree of beta- blockade and recovery from beta-blockage after termi nation of the i nfu¬ sion. The doses were spaced at 10-miπute intervals and were given before, during and following the i nfusion of test compounds . The infu¬ sion rate was adjusted so that the end of the 3-hour i nfusion period the degree of isoproterenol inhi bition averaged about 50% of control . The results of the 40-minute nfusion are shown in Table IV, and the results of the 3-hour infusion are shown in Table V. TABLE IV Test Compound ( Numerical Designation Indicates Previous Example Which Describes Preparation Potency 80% Recovery Number of Example of Compound) mg/kq/40 min Time Experiments XXXIII 1 3.7 + 1.3 34 + 11 3 XXXIV II 5.7 + 1.6 56 + 6 3 XXXV X 0.14 + .04 12 + 1 3 XXXVI III 2.3 + 0.6 20 + 5 4 XXXVII IV 1.35 + 0.52 12 + 2 4 XXXV II I V 4.5 + 1.5 1 ± 2 3 XXXIX IX 0.176 + 0.02 15 + 2 4 Propranolol 0.06 + .01 42 + 9 10 Practolol 61 TABLE V Test Compound (Numerical Designation Indicates Previous Example Which Describes Preparation Potency 80% Recovery Number of Example of Compound) mq/kq/180 min Time Experiments XL XI I I 0.45 29 + 6 4 XLI V I 31.0 + 7.0 14 + 3 5 XLII IV 9.p 12 + 3 13 XLIII IX 1.1 15 + 2 5 XLIV XI 2.5 + 0.4 30 + 4 3 XLV XVI 3.5 + 0.7 36 + 5 5 XL I XV 12.8 >60 4 XLV11 X 0.90 22 + 5 6 XLVIII V 30.4 15 + 3 9 Propranolol 0.225 >60 6 Practolol >60 EXAMPLE XLIX - LVII 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 homogenate. 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, ImL of a solution containing 5 μg of the test compound was added to 1 L of whole 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. Acetonitr le (2 L) 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 chromatography, using a mobile phase of 60% acetonitr le/40% 0.05M sodium phosphate buffer (pH 6.6), a U.V. detector, and a Waters u 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 VI. 3 O Q. _= O ___ .-I ___; ?5 C_5 Q. X ε _I X X

Claims: CLAI S 1. A method for the treatment or prophyl axis of cardi ac dis¬ orders in a mammal , comprisi ng admi nistering to such mammal a short- acting β-blocki ng compound of the formul a wherein R is lower alkyl, lower cycloakyl, lower alkenyl, lower alkyl or aryl carboxymethyl, lower haloalkyl, aryl, or aralkyl; n is an integer from 0 to about 10; x is an integer from 1 to 3, provided that when x is 0 II greater than 1, different occurrances of the R-0-C-(CH 2 ) - group may be the same or different; Ar is unsubstituted aromatic or aromatic substi¬ tuted with lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halogen, acetamido, amino, nitro, lower alkylamino, hydroxy, lower hydroxyalkyl, or cyano; R-, is lower alkyl or aralkyl; or a phar aceuti- cally acceptable salt thereof. 2. The method of claim 1 wherein n is an integer from 0 to about 5, and x is 1 or 2. 3. The method of claim 1 wherein Ar is phenyl; x is 1 or 2, n 0 II is an integer from 0 to about 3 and at least one of the R-0-C-(CH 2 ) - OH groups is in the ortho position with respect to the - O-O-L-CH-D-L-NH^ group. 4. The method of claim 1 wherein Ar is phenyl; x is 1 or 2; n 0 II is an integer from 1 to about 3; and at least one of the R-0-C-( CH2) n " 0H groups is in the para position with respect to the - 0-CH 2 -CH-CH 2 -NH-R 1 group. 5. The method of claim 3 or 4 wherein R is lower alkyl of from 1 to about 5 carbon atoms. 6. The method of claim 1 wherein the compound is of the formula OH wherein n is an integer from 0 to about 3; R is lower alkyl from 1 to about 5 carbon atoms or lower alkenyl of from 2 to about 5 carbon atoms; Y is hydrogen, lower alkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, lower alkynyl of from 2 to about 5 carbon atoms, lower alkoxy of from 1 to about 5 carbon atoms, halogen, acetamido, amino, nitro, lower alkylamino of from 1 to about 5 carbon atoms, hydroxy, lower hydroxyalkyl of from 1 to about 5 carbon atoms or cyano; and R-, is lower alkyl of from 1 to about 5 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. 7. The method of claim 1 wherein the compound is of the formula OH wherein n is an integer from 1 to about 3: R is lower alkyl of from 1 to about 5 carbon atoms or lower alkenyl of from 2 to about 5 carbon atoms; Y is hydrogen, lower alkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, lower alkoxy of from 1 to about 5 carbon atoms, halogen, acetamido, amino, nitro, alkylamino, hydroxy, lower hydroxyalkyl of from 1 to about 5 carbon atoms or cyano; and R is lower alkyl of from 1 to about 5 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. 8. The method of claims 1, 2, 3, 4, 5, 6, or 7 wherein the compound is administered parenterally. 9. The method of cl aim 8 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. 10. The method of claim 8 wherein the compound is administered by intravenous injection or 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. 11. A compound of the formula -CH 2 -N-R 1 wherein R is lower alkyl , lower cycloal kyl , lower al kenyl , lower alky! or aryl carboxymethyl, lower haloalkyl , or aralkyl ; n is an integer from 1 to about 10; x is an integer from 1 to 3, prov ded that when x is 0 II greater than 1, different occurrances of the R-0-C-( CH 2 ) - group may be the same or different; Ar is unsubstituted aromatic or aromatic substi¬ tuted with lower alkyl , lower al kenyl , lower al koxy, halogen, acetamido, amino, nitro lower alkylamino, hydroxy, lower hydroxyal kyl , or cyano; R^ is lower alkyl or aralkyl; or a pharmaceutical ly acceptable salt thereof . 12. The compound of cl aim 11 wherei n n is an integer from 1 to about 5, and x is 1 or 2. 13. The compound of claim 11 wherein Ar is phenyl; x is 1 or 2, 0 II n is an integer from 1 to about 3 and at least one of the R-0-C-(CH 2 ) n - OH I group is in the ortho position with respect to the -0-CH 2 -CH-NH-R group. 14. The compound of claim 11 wherein Ar is phenyl, x is 1 or 2; 0 II n is an integer from 1 to about 3; and at least one of the R-0-C-(CH 2 ) n - OH groups is in the para position with respect to the -0-CH 2 -CH-CH 2 -NH-R group. 15. The compound of claim 13 or 14 wherein R is lower alkyl of from 1 to about 5 carbon atoms. 16. The compound of claim 11 of the formula OH 0-CH 2 -CH-CH 2 -NH-R 1 wherein n is an integer from 0 to about 3; R is lower alkyl of from 1 to about 5 carbon atoms or lower alkenyl of from 1 to about 5 carbon atoms; Y is hydrogen, lower alkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, lower alkynyl of from 2 to about 5 carbon atoms, lower alkoxy of from 1 to about 5 carbon atoms, h-alogen, acetamido, amino, nitro, alkylamino, hydroxy, lower hydroxy¬ alkyl of from 1 to about 5 carbon atoms, cyano, or a group of the formula 0 R-0-C-(CH 2 ) n _ _._ H ι 17. The compound of cl aim 11 of the formul a OH wherein n is an integer from 1 to about 3; R is lower alkyl of from 1 to about 5 carbon atoms or lower alkenyl of from 1 to about 5 carbon atoms; Y is hydrogen, lower alkyl of from 1 to about 5 carbon atoms; Y is hydrogen, lower alkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, lower alkoxy of from 1 to about 5 carbon atoms, halogen, acetamido, amino, nitro, alkylamino, hydroxy, lower hydroxyalkyl of from 1 to about 5 carbon atoms or cyano. 18. The compound of claim 17 wherein R is methyl; Y is hydrogen; n is an integer from 1 to about 3; and R, is isopropyl, t-butyl, or 3,4- dimethoxyphenethyl. 20. The compound of claim 17 wherein R is methyl; Y is halogen or lower alkyl of from 1 to about 5 carbon atoms; n is 2; and R, is isopropyl, t-butyl, or 3,4-dimethoxyphenethyl. 0 II 21. The compound of cl aim 17 wherei n R is methyl ; Y is -C-O-Q-L, n is 2, and R^ is isopropyl , t-butyl , or 3,4-dimethoxyphenethyl . 22. A process for producing a compound of the formula OH R0C-(CH 2 )- -Ar-O-CHg-CH-CHg-N-R j H wherein R is lower alkyl, lower cycloalkyl, lower alkenyl, lower alkyl or aryl carboxymethyl, lower haloalkyl, or aralkyl; n is an integer from 1 to about 10; x is an integer from 1 to 3, provided that when x is 0 II greater than 1, different occurrances of the R-0-C-(CH 2 ) n - group may be the same or different; Ar is unsubstituted aromatic or aromatic substi¬ tuted with lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halogen, acetamido, amino, nitro, lower alkylamino, hydroxy, lower hydroxyalkyl, or cyano; , is lower alkyl or aralkyl; or a pharma¬ ceutically acceptable salt thereof; which comprises reacting an appro¬ priate phenol derivative of the formula wherein R, n, x, and Ar are defined as hereinbefore, with epichloro¬ hydrin by heating the reactants to reflux in an appropriate solvent in the presence of a base to form a l,2-epoxy-3-aryloxypropane derivative of the formula 0 R0C-(CH 2 } Ar-0-CH 2 -C AH-CH 2 wherein R, n, x, and Ar are defined as hereinbefore, which is then reacted with an amine of the formula R,-NH 2 wherein R, is defined as hereinbefore, by heating the reactants to reflux in an appropriate solvent to give the final product which may optionally be converted to a pharmaceutically acceptable salt by reaction with an appropriate acid. - u-U- 23. A process according to the claim 22 for producing a com¬ pound of the formula OH R0C-(CH 2 )- Ar-0-CH„-CH-CH, ■N-R 1 wherein R, Ar, and R, are defined as before, n is an integer from 1 to about 5, and x is 1 or 2. 24. A process according to claim 22 for producing a compound of the formula OH R0C-(CH 2 )- Ar-0-CH 2 -CH-CH 2 -N-R 1 H wherein R and" R, are defined as before; Ar is phenyl; x is 1 or 2, n is an integer fr groups is in group. 25. A process according to claim 22 for producing a compound of the formula OH ROC-(O- 2)-n Ar-0-CH 2 -CH-CH 2 -N-R 1 H wherein R and R 1 are defined as before; Ar is phenyl; x is 1 or 2, n is 1 0 an integer from 1 to about 3 and at least one of the R-0-C-(CH 9 ) - OH ά n I groups is in the para position with respect to the -0-Q-L-CH-NH-R group. 26. A process according to claim 22 for producing a compound of the formula wherein R is lower alkyl of from 1 to about 5 carbon atoms and n, x, Ar, and R, are def ned as before. 27. A process according to claim 22 for producing a compound of the formula OH wherein n s an integer from 0 to about 3; R is lower alkyl of from 1 to about 5 carbon atoms or lower alkenyl of from 1 to about 5 carbon atoms; Y is hydrogen, lower alkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, lower alkynyl of from 2 to about 5 carbon atoms, lower al oxy of from 1 to about 5 carbon atoms, halogen, acetamido, amino, nitro, alkylamino, hydroxy, lower hydroxy¬ alkyl of from 1 to about 5 carbon atoms, cyano, or a group of the formula R-0-C-(CH 2 ) n - wherein R is defined as hereinbefore, and R, is lower alkyl of from 1 to about 5 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. 28. A process according to cl im 22 for producing a compound of the formula 0H wherein n is an integer from 1 to about 3; R is lower alkyl of from 1 to about 5 carbon atoms or lower alkenyl of from 1 to about 5 carbon atoms; Y is hydrogen, lower alkyl of from 1 to about 5 carbon atoms; Y is hydrogen, lower alkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, lower alkoxy of from 1 to about 5 carbon atoms, halogen, acetamido, amino, nitro, alkylamino, hydroxy, lower hydroxyalkyl of from 1 to about 5 carbon atoms or cyano; and R, is lower alkyl of from 1 to about 5 carbon atoms or aralkyl wherein the alkyl portion contains from 1 to about 5 carbon atoms and the aryl portion contains from 1 to about 10 carbon atoms. 29. A process according to claim 28 for producing a compound of the formula OH wherein R is methyl; Y is hydrogen; n is an integer from 1 to about 3, and R, is isopropyl, t-butyl, or 3,4-dimethoxyphenethyl. 30. A process according to claim 28 for producing a compound of the formula OH O ?I wherein R is methyl; Y is halogen or lower alkyl of from 1 to about 5 carbon atoms; n is 2; and R, is isopropyl, t-butyl, or 3-4-dimethoxy- phenethyl. 30. A process according to claim 28 for producing a compound of the formula OH wherein R is methyl ; Y is -C00CH 3 , n is 2, and R^ ^ is isopropyl , t-butyl , or 3,4-dimethoxyphenethyl .

Inventors: BORGMAN ROBERT J, ERHARDT PAUL W, O DONNELL JOHN P
Applicants: AMERICAN HOSPITAL SUPPLY CORP
Application year: 1981
Main classification: A61K31
IPC codes: C07C9, C07C67, C07C213, C07C217, C07C233, C07C253, C07D303