AU547994B2 - Creación de Inventos y Patentes con Inteligencia Artificial

AU547994B2 – Method for treatment or prophylaxis of cardiac disorders
– Google Patents

AU547994B2 – Method for treatment or prophylaxis of cardiac disorders
– Google Patents
Method for treatment or prophylaxis of cardiac disorders

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Publication number
AU547994B2

AU547994B2
AU78967/81A
AU7896781A
AU547994B2
AU 547994 B2
AU547994 B2
AU 547994B2
AU 78967/81 A
AU78967/81 A
AU 78967/81A
AU 7896781 A
AU7896781 A
AU 7896781A
AU 547994 B2
AU547994 B2
AU 547994B2
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AU
Australia
Prior art keywords
compound
formula
carbon atoms
lower alkyl
acceptable salt
Prior art date
1980-11-28
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Application number
AU78967/81A
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AU7896781A
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Inventor
S. Erhardt P.W. Borgman R.J. O’donnell J.P. Kam
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Bristol Myers Squibb Pharma Co

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American Hospital Supply Corp
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1980-11-28
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1981-11-16
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1985-11-14

1981-11-16
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American Hospital Supply Corp

1982-06-17
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patent/AU7896781A/en

1985-11-14
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1985-11-14
Publication of AU547994B2
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1992-05-21
Assigned to E.I. DU PONT DE NEMOURS AND COMPANY
reassignment
E.I. DU PONT DE NEMOURS AND COMPANY
Alteration of Name(s) in Register under S187
Assignors: AMERICAN HOSPITAL SUPPLY CORP.

1992-05-28
Assigned to DU PONT MERCK PHARMACEUTICAL COMPANY, THE
reassignment
DU PONT MERCK PHARMACEUTICAL COMPANY, THE
Alteration of Name(s) in Register under S187
Assignors: E.I. DU PONT DE NEMOURS AND COMPANY

2001-11-16
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Classifications

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07D—HETEROCYCLIC COMPOUNDS

C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members

C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members

C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom

C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms

C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms

C07D213/30—Oxygen atoms

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS

C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton

C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07D—HETEROCYCLIC COMPOUNDS

C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings

C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

C07D309/10—Oxygen atoms

C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers

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 β-adrenergic blocking agents and to compounds useful in 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 prevention of further tissue damage and can relieve angina pectoris.
β-Adrenergic stimulation may also aggravate or cause arrhythmias because of increased levels of catechoiamines. 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 β1, receptors, and those associated with vasodilation and bronchodilation are β2 receptors. Selective β1- blockers are preferred for the treatment of cardiac disorders because they may have less potential to cause hypertension or

bronchoconstriction. A number of β1 selective adrenergic blocking agents have been discovered. Smith, L.H., J. Appl . Chem. Biotechnol., 28, 201-212 (1978). Most of such compounds are structural variations of 1-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 infarction. Conventional β- blocking agents can be employed for such treatment, 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-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 or prophylaxis of cardiac disorders in a mammal comprising administering to such mammal a short-acting β-blocking compound of the formula:
wherein X may be

; 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, acetamido, amino, nitro, alkyl amino, hydroxy, hydroxyalkyl, cyano, or a group of the formula

wherein R2 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: –

wherein X represents an ester function of the formula

; 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 about 1 to about 5 carbon atoms and the aryl portion represents substituted or unsubstituted monocyclic or polycyclic aromatic or hetεrocyclic ring systems of from 6 to about 10 carbon atoms, such as 3,4-dimethoxyphenethyl, 4-carbamoylphenoxyethyl, 1,1-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

wherein R2 is lower alkyl, aryl or aralkyl and 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.
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-dimethoxyphenethyl; 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

wherein R2 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
present invention, X is R is selected from the group

consisti ng of i sopropyl , t-butyl , and 3 ,4-dimethoxyphenethyl ; and Ar is 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

wherein Z ia a straight or branched chain hydrocarbon of from 1 to about 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 ester function, X.

For compounds of the formulas hereinbefore described in which X
the following reaction scheme may be employed:

In the above scheme, R1 is eliminated when X is

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-methoxybenzyloxycarbonyl 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 treatment with a mineral acid.
For compounds in which X is the

following reaction scheme may be employed:
el imi nated when X i s

Compounds i n whi ch Ar is not substituted with an ester-contai ni ng
group and in which X is or are advantageously

prepared by either of the following two schemes:

*eliminated when X is .

This latter scheme is particularly preferred for compounds in which R is an ester-contai ning 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 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 LXXX-CIV. The compounds have been found to be generally nontoxic 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. In vitro 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-blocking 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:

3-[(3,4-Dimethoxyohenethyl) amino]-2-hydroxypropionic 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 Na2CO3. The aqueous section was extracted with 2×500 ml of chloroform and neutralized to pH 7 with diluted HCl. The solution was evaporated to dryness and the residue was recrystallized 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, C13H19O5N.
3-[[N-(3,4-Dimethoxyphenethyl)-N-(4-methoxybenzyloxycarbonyl)] 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-H2O (1:1) was added 0.23g (2.73, mmole) of NaHCO3 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 2×20 ml of ether. Evaporation of the ether gave 0.08g (36%) of the product. The NMR and IR spectra were consistent with the assigned structure.
3-[[N-(3,4-Dimethoxyphenethyl)-N-(4-methoxybenzyloxycarbonyl)]amino]-2-[(tetrahydro-2-pyranyl)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 neutralized with concentrated NH4OH. 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 NH4OH, filtered, and the ether was removed in 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-Dimethoxyphenethyl)-N-(4-methoxybenzyloxycarbonyl)]- amino]-2-[(tetrahydro-2-pyranyl)oxy]propionate.
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 carbonyldiimidazole 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 imidazole. The reaction mixture was stirred for 10 hours and partitioned between 2×100 ml of ether and 100 ml of water. Evaporation of the ether gave an oil which was purified by column chromatography (silica gel/EtOAc: hexane=1:1) to give 1.1g (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 C33H39O9N.
N-(3,4-Dimethoxyphenethyl)-N-[(2-hydroxy-2-phenoxycarbonyl)ethyl-] amine Hydrochloride. A mixture of 1g 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 C19H24O5NCl.
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.

Example V This example describes the synthesis of a compound of the following formula:

2 -Methoxybenzyl 3-[[N-(3,4-Dimethoxyphenethyl)]amino]-2-hydroxypropionate
To 3g of the 3-(3,4-dimethoxyphenethyl)amino-2-hydroxypropionic acid prepared in Example I was added 200 ml of benzene and 20 ml of 2- methoxybenzyl 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 NaHCO3 and extracted with CHCl3. Evaporation of the CHCl3, gave an oily residue which after chromotography on a column (silica gel/Et2O:EtOH=5:1) gave 1g (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 C21H27O6N.
Example VI This example describes the synthesis of a compound of the formula:

2,3 Epoxypropyl Benzoate
A mixture containing 14.8g (0.2 mole) of glycidol, 150 ml of anhydrous ether, 16g (0.4 mole) of pyridine and 28g (0.2 mole) of benzoyl chloride was stirred at room temperature for 2 hours. The mixture was filtered and the ether was evciporated to leave 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-(Isopropylamino)-2-hydroxy]propyl Benzoate Hvdrochloride To 1g of the epoxide from the previous expεriment was added 10g 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:CH2Cl2=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 white 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 C13H26 O3NCl

Examples VII – XIII
The experiment of Example VI was repeated in all essential details to produce the compounds described in Table II, except that the reactants described in the second and third columns of the table were substituted for benzoyl chloride and isopropyl amine respectively. The compound of Example VIII was purified by recrystallization from acetone, and the compound of Example IX was purified by recrystallization from toluene. All of the compounds were prepared as the hydrochloride 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.

Example XIV This example describes an alternate synthesis of the compound in Example XII.
3-(Isopropylamino)1 ,2-propanediol
A mixture of 37g (0.5 mole) of glycidol and 35.4g (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 product: b.p. 80°C/0.1mm Hg. The KMR and IR spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula C6H15O2N.
[3-(Isopropylamino)-2-hydroxy]propyl 2-chlorobenzoate hydrochloride
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 13.1g (75 mmole) of 2-chlorobenzoyl chloride. The mixture was stirred at room temperature for 2 hours and 100 ml of water was added. The Ryridine was evaporated in vacuo at 55-60°C and the aqueous solution was washed with 100 ml of ether. The aqueous layer was then basified with K2CO3, and extracted with methylene chloride.
The methylene chloride layer was acidified with ether-HCl and evaporated 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 the table were substituted for isopropyl amine and 2-chlorobenzoyl chloride respectively. The compounds were prepared as the acid addition salts or free bases as indicated in Table III. Each of the compounds was identified by NNR and IR spectroscopy, elemental analysis, and melting point.

Example LIV This example describes the synthesis of a compound of the formula

@2-Hydroxy-3-(isopropyl amino)∅propyl 4-aminobenzoate hydrochloride
To 20 mg of 10% Pd-C in 30 ml 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 C13H21N2O3Cl.
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.

Example LXII This example describes the synthesis of a compound of the formula

[2-Hydroxy-3-(isopropyl amino)] propyl 4-(acetamido) benzoate hydrochloride
To 1g (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% K2CO3 and 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 C15H23N2O4Cl.
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)] propyl 3-(acetamido)-benzoate oxalate; m.p. 130-132.5°C.
Example LXIV This example describes the synthesis of a compound of the formula

[2-Hydroxy-3(isopropylamino)] propyl 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% K2CO3 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 (6%) 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 C14H21NO4.
Example LXV This example describes the synthesis of a compound of the formula

3-[N-(n-propyl)-N-benzyl]amino-1,2-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-Benzyl-N-(n-propyl)]amino-2-hydroxy] propyl 4-nitrobenzoate
The diol from the previous experiment was allowed to react with pnitrobenzoyl chloride in a similar manner, as described in the preparati-on of [2-Hydroxy-3-(isopropylamino)] propyl 2-chlorobenzoate hydrochloride in Example XIV. The product was purified by chromatography (silica gel/ether:hexane = 4:2). Yield was 65%.
[2-Hydroxy-3-(n-propyl)amino]propyl 4-aminobenzoate 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 H2 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; 2.4g (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 C15H22N2O7.

Example LXVI This example describes the synthesis of a compound of the formula

3-[N-[(4-methoxybenzyl)oxycarbonyl]-N-(3,4-dimethoxyphenethyl)] amino-1,2-propanediol 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 evaporation of the dioxane in vacuo, the residue was partitioned between water and CHCl3. Evaporation of CHCl3 gave an oil which was purified by chromatography (silica gel/10% ethanol in methylene chloride) to give 13g (30.5%) of product.
[2-Hydroxy-3-[[N-[(4-Methoxybenzyl)oxycarbonyl]-N-(3,4-dimethoxy- phenethyl)]amino] propyl 4-formyl benzoate The diol from the previous experiment was allowed to react with 4-formylbenzoyl chloride in a similar manner as described in the preparation of [2-Hydroxy-3-(isopropylamino)] propyl 2-chlorobenzoate 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)amino]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% K2CO3 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. 164-164.5°C. The NMR and IR spectra were consistent with the assigned structure and the

elemental analysis was consistent with the empirical formula C23H29NO10.
Example LXVII
The experiment of Example I is employed to produce a compound of the formula

The procedure is repeated in all essential details, except 4-hydroxy-5-chloropentanoic acid is substituted for B-chlorolactic acid and isopropyl amine is substituted for 3,4-dimethoxyphenethylamine to produce the intermediate 5-isopropylamino-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) pA2 Cardioselectivity
Example Atria Trachea KB(Trachea)/KB(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 – –
LXXIII XIX 6.5 7.0 -3
LXX IV XXI 6.8 7.2 -2.5
LXXV LV 6.4 6.0 -2.5
LXXVI VI I I 6.8 7.3 -3
LXXV I I XX 6.6 7.3 -5
LXXVIII XXII 6.1 6.2 1 LXXIX X 6.8 6.8 1

TABLE V (Cont’d)
Test Compound
(Numerical designation indicates previous example which describes preparation of compound) pA2 Cardioselectiv i ty
Example Atria Trachea KB(Trachea)/KB(Atria)
LXXX XXIII 6.0 6.3 -2
LXXXl XXIV 5.7 5.7 1
LXXXII LV I 6.0 7.2 -2.5
LXXX I I I LXIV 6.2 6.3 1
LXXX IV LXII 5.0 5.2 4
LXXXV XXX <6.0 - - - - LXXXVI XXXVII 6.0 7.7 -0 LXXXVII XXXIX 6.0 8.0 -16 LXXXVIII XXXVIII 7.2 7.8 -4 LXXXIX LIII 6.0 - - - - XC VI I 7.0 6.8 5 TABLE V (Cont'd) Test Compound (Numerical designation indicates previous example which describes preparation of compound) pA2 Cardioselectivity Example Atria Trachea KB(Trachea)/KB(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 XCV XXXV 7.0 6.7 2 XCVI XI 6.6 6.0 4 XCVII LXVI < 5.5 - - - - XCVIII I 5. 9 5. 9 1 XCIX I I 5. 9 - - - - C V inactive 5.0 - - TABLE V (Cont'd) Test Compound (Numerical designation indicates previous example which describes preparation of compound) pA2 Cardioselectivity Example Atria Trachea KB(Trachea)/KB(Atria) Cl XV 6.6 7.0 -2.5 CII XVI 6.4 6.6 -2 CIII LXV 5.9 - - - - Examples 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% O2-5% CO2) 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 spontaneously under a loading tension of approximately 0.5 gm. Instrinsic 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 phentol amine, tropolone and cocaine. Active tension was generated by addition of carbachol (3.0 × 10-7M) and decreases in tension in response to isoproterenol were 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 pA2 values (-log Kg) by the method of Furchgott, The Pharmacological Differentiation of Adrenergic Receptors, Ann. N.Y. Acad. Sci., 139: 553-570 (1967). Comparision of blockade of right atrial and tracheal responses to isoproterenol 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 atri a (10(pA2atri a - PA2 trachea) ) A ratio greater than one i ndicates 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 _ re e- .^ Examples CIV - CXXVIII The duration of beta-blockade was determined in vivo using pentobarbital-anesthetized dogs instrumented for measurement of heart rate using a Beckman 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 were used. The first employed a 40-minute infusion of test compound and the second used a 3-hour infusion of test compound. In the 40 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 quantitated. 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 quantitate 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 i nfus ion model , bol us 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 (mg/kg) 50% 80% 100% Erevious example which describes preparation of compound) CIV XV 1.5 18 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 CVI l 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 CX 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 ± 1 16 ± 2 25 ± 3 CXIII XII 1.75 19 30 51 CX IV XVI I I 1.5 - - 8 ± 1 - - Propranolol - - 23 ± 4 42 ± 0 50 ± 9 Tabl e 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) CXVII XXXIX 3.6±O.6 60±2 17±3 (5) CXVIII XVIII 19.08 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 83 >60 (2)
CXXIII XXXI 40.7 85 >60 (2)
CXXIV XX111 37.6 67±6 >60 (3)

Table VI I (Cont ‘d)
Potency 00% Recovery Time
Example test Compound (mg/kg/180 min) %I* (min) No. of Experiments
CXXV XXXVIII 3.2 67 35, >60 (2)
CXXVI LVI 4.5 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.

Examples CXXIX – CXLI I These examples describe experiments which demonstrate the disappearance 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 (T1/2), 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 added to 1 ml. 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. 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 chromatografphy, using a mobile phase of 60% acetonitrile/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 VIII
Test Compound (numerical designation indicates previous example which describes preparation of compound) T1/2 (minutes)
Example Human Dog Dog Whole Blood Whole Blood Liver Homogenate
CXX IX XVI I I 1.7±0.6 7 – –
CXXX XII 1.7±0.6 20±15 12±4
CXXXI VI 2.3±0.6 6.0±2 0.0±3.5
CXXXII XX 3.5±0.9 4 – –
CXXXIII X 6±0 67±24 10±4
CXXXIV XIX 8±4 50 – –
CXXXV XXIII 55±5 150±30 37±20 CXXXYI XV I I >> 180 >> 180 147±69
CXXXVII XXXIX 1.4±1 6±2 17±7
CXXXVIII XXXVII 5.3±1 5.5 – –
CXXXIX XLII 5.5±2.6 150 – –

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 (32)

1. A method for the treatment or prophylaxis of cardiac disorders in a mammal, comprising administering to such mammal a shortacting β- blocking compound of the formula
wherein X is -; R is lower alkyl, lower alkenyl or aralkyl; R1 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
wherein R2 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; R1, 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; R1 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
wherein R2 is lower alkyl of from 1 to about 5 carbon atoms and n is an integer from 0 to about 5 4. The method of claim 1 wherein X is -; 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.

5. The method of claim 1 further comprising administering a compound in which R is a group of the formula wherein Z is a straight or branched chain hydrocarbon of from 1 to about 10 carbon atoms, and R2 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 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.

9. A compound of the formula
wherein X is 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, acetamido, amino, nitro, alkyl amino, hydroxy, hydroxyalkyl, cyano, or a group of the formula wherein R2 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; R11 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; R1, is methylene; and Ar is unsubstituted phenyl or phenyl substituted with lower alkyl of from 1 to about 5 carbon atoms, fluoro, chloro, nitrcf, or a. group of the formula
wherein R2 is lower alkyl of from 1 to about 5 carbon atoms and n is an integer from 0 to about 5.

12. The compound of claim 9 wherein X is 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.

13. The compound of claim 9 in which R is a group of the formu l a
wherein Z is a straight or branchεd chain hydrocarbon from 1 to about 10 carbon atoms, and R2 is lower alkyl from 1 to about 5 carbon atoms.

14. A compound of the formula
F 0 OH
//~\ C-0-CH2-CH-CH2-N-R wherein R is isopropyl or t-butyl, or a pharmaceutically acceptable salt thereof.

15. A compound of the formula /—, 0 OH y \V-C-0-CH2-CH-CH2-N-R 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.

20. A process for preparing a compound of the formula

wherein X is R is lower alkyl, lower alkenyl, or aralkyl; R 1 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 the formula

wherein. R2 is lower alkyl, aryl, or aralkyl and n is an integer from 0 to about 10; or. a pharmaceutically acceptable salt thereof, which comprises reacting a compound of the formula Ar OH, wherein Ar .is defined as hereinbefore, with a compound of the formula

wherein X and R are defined as hereinbefore 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 optional ly be converted to a pharmaceutically acceptable salt by reaction with an appropriate acid.

21. A process for preparing a compound of the formula

~÷- i wherein X is ; R is lower alkyl, lower alkenyl, or aralkyl; R1 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

wherein R2 is lower alkyl, aryl, or aralkyl and n is an integεr from 0 to about 10; or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of the formula Ar-R1-OH, wherein Ar and R1 are defined as hereinbefore, with a compound of the formula

wherein R, is lower alkylene or a direct bond, by heating the 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 pharmaceutically acceptable salt by reaction with an appropriate acid.

22. A process for preparing a compound of the formula

– wherein X is ; R is lower alkyl, lower alkenyl, or aralkyl; R1 is lower alkylene; and Ar is unsubstituted aromatic or aromatic substituted with lower alkyl, lower alkenyl, Tower alkynyl, lower alkoxy, halogen, acetamido, amino, nitro, alkamino, hydroxy, hydroxyal kyl , or cyano; or a pharmaceutically acceptable salt thereof, which comprises: a) reacting a compound of the formula wherein Ar and X are defined as hereinbefore with a compound of the formula H2N-R, wherein R is defined as hereinbefore, by heating the reactants to reflux to give the final product which may optionally be converted to a pharmaceutically acceptable salt by reaction with an appropriate acid; or
b) reacting a compound of the formula wherεin R and R1 are defined as hereinbefore, with an acyl chloride of the
formula , wherein R1 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
of the formula 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; R1 is lower alkylene of from 1 to about 5 carbon atoms.

24. The process of claim 20, 21 or 22 for producing a compound
of the formula 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; R1 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 _ _ wherein R2 is lower alkyl 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
formula wherein X is 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
of the formula wherein X and Ar are defined as before and R is a group of the formula wherein Z is a straight or branched chain hydrocarbon from 1 to about 10 carbon atoms, and R2 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 formula
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.

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