CA1272733A - Compositions for treating glaucoma - Google Patents

Abstract

ABSTRACT

A compound of the formula:

or a pharmaceutically acceptable salt thereof; wherein R is lower hydroxyalkyl or lower alkynyl, and Ar is unsubstituted phenyl or phenyl substituted with lower alkyl of from 1 to about 5 carbon atoms, fluoro, chloro, nitro, hydroxy, amino, acyloxy, wherein the acyl portion is alkanoyl of from 2 to about 5 carbon atoms, or unsubstituted benzoyl or benzoyl sub-stituted with halogen, lower alkoxy, lower alkyl, hydroxy or a group of the formula:

Description

Backgrouncl of the Invention ____ _ The present invention relates to a method for the treatment of glaucoma. More particularly, the invention relates to a novel method of treatment of glaucoma or lowering of intraocular pressure by topically administering beta-adrenergic blocking agents to the eye.
Glaucoma is a condition of the eye characterized by increased intraocular pressure~ Untreated, the condition can eventually lead to irreversible retinal damage and blindness. Conventional therapy for glaucoma has involved topical administration of pilocarpine and/or epinephrine, administered to the eye several times daily.
Various beta-blocking agents may also be used to lower intraocular pressure. Such use is described, for example, in reviews by W. P. Boger in Dru~s, 18, 25-32 (1979) and by T. J. Zimmerman and W. P. Boger in Survey Ophthalmol. 23(b), 347 (1979). The use of beta-blockers -for the treatment of glaucoma is also described in the patent literature. For example, U S. Patent No.
4,195,085 to Stone discloses a method for treatment of glaucoma by the ocular administration of a beta-blocking compound, timolol maleate. U.S~ Patent No. 4,127,674 discloses treating glaucoma with labetalol, a known antagonist of both alpha and beta adrenergic receptors.
Howeverl these methods also possess significant drawbacks, in that the absorption of the beta-blocking compound into the systemic circulation can cause undesirable side effects. Such side effects result from prolonged beta-blocking action on the heartl bronchioles and blood vessels. For example, according to Physicians' Desk Reference, Charles E. Baker, Jr., 35th Edition, 1981, p. 1233, adverse reactions to the topical use of timolol maleate can include bronchospasm, --2~

heart failure, as well as cardiac conduction deEects.
Accordingly, there is a need for a method of treatment of glaucoma or for lowering intraocular pressure which is relatively free of unwanted systemic side-effects.
Certain bet_-blocking agents which contain enzyrnatically labile ester groups are known to exhibit short-acting beta-blocking effects in the systemic circulation. Such short-acting beta-blocking compounds (SAABs) have been suggested for treatment or prophylaxis of cardiac disorders as a means for reducing heart work or improving rhythmicity for a short duration. Such short-acting beta-blocking compounds avoid the sometimes counterproductive effects of conventional beta-blocking agents, whose effects are long-lived and therefore difficult to precisely control.
Summary of the Invention In accordance with the present invention, disclosed herein is a method for the treatment of glaucoma or for lowering intraocular pressure in a mammal, comprising topically administering to the eye of such mammal a beta-blocking compound of the formula:
O 0~
Il I
;9r~C-C)-CH2-CH-CH2-NHR

wherein R represents lower alkyl of straight or branched carbon chains from 1 to about 10 carbon atoms;
cycloalkyl of from 3 to about 7 carbon atoms; alkenyl of from about 2 to about 10 carbon atoms; alkynyl of from 3 to about 10 carbon atoms; hydroxyalkyl of from 2 to about 7 carbon atoms; aralkyl, wherein the alkyl portion contains from 1 to about 5 carbon atoms, and the aryl portion represents substituted or unsubstituted monocyclic or polycyclic aromatic or heterocyclic ring -3- ~

systems of from about 6 to about 10 carbon atoms; a group of the formula o Il _z--C-O-Rl wherein Z represents lower alkylene of straight or branched carbon chains of from 1 to about 10 carbon atoms, and Rl is lower alkyl of from 1 to about 5 carbon atoms; and Ar represents substituted or unsubstituted aromatic; or a pharmaceutically-acceptable salt thereof.

Detailed DescrLption of the Invention The above-mentioned short-acting beta-blocking compounds effectively reduce intraocular pressure in the eyes of mammals when topically administered. Because of 1~ their short-lived duration of action in the systemic circulation, toxic side-effects produced by their migration out of the eye are consequently reduced. It has further been discovered that certain of these compounds show an increased longevity of effect when present in the ocular fluid compared to the duration of their systemic effects. Consequently, the present invention resides in the treatment of glaucoma or lo~ering intraocular pressure with a beta-blocking compound which exhibits relatively long duration of action while in the ocular fluid, but which is subject to relatively rapid breakdown into inactive metabolites upon passage to the systemic circulation~
Compounds administered by the method of the present inventlon are represented by the formula:
O OH
Il I
Ar-C-O-CH2-CH-CH2-NHR

wherein R represents lower alkyl of straight or branched carbon chains from 1 to about 10 carbon atoms;
cycloalkyl of from 3 to about 7 carbon atoms; alkenyl of from 2 to about 10 carbon atoms; alkynyl of from 2 to about 10 carbon atoms; hydroxyalkyl of from 2 to about 7 carbon atoms; 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 aromatic or heterocyclic ring systems of from 6 to about 10 carbon atoms, such as benzyl, phenethyl, 3,4-dimethoxyphenethyl, 1,1-dimethyl-

2-(3-indolyl) ethyl, and the like; and Ar represents substituted or unsubstituted aromatic, including monocyclic, polycyclic and heterocyclic ring systems.
Aromatic (Ar) substituents may include lower alkyl, lower alkenyl r lower alkynyl, lower alkoxy, halogen r acetamido, amino, nitro, lower alkylamino, hydroxy, hydroxyalkyl, cyano, methylenedioxy, acyloxy, wherein the acyl portion is a straight or branched chain alkanoyl o from 1 to about 7 carbon atoms or aroyl of from 6 to about 10 carbon atoms, optionally substituted by halogen, lower alkoxy, lower alkyl, acetamido, cyano or hydroxy/ and groups of the formula o ll Rl-O-c-(cH2)n wherein R1 is lower alkyl, aryl or aralkyl and n is an integer from 0 to about 10. The compounds described herein are not limited to any particular stereoisomeric configuration. Such compounds may be administered as their pharmaceutically acceptable acid addition salts, e.g., as the hydrochloride, sulfater phosphate, oxalater gluconate, tartrate, et cetera.

-s-In preferred compounds R is lower alkyl o from 1 to about 5 carbon atomst such as isopropyl, n-butyl, t-butyl~ n-pentyl, and the like; alkynyl of from 3 to about 5 carbon atoms~ such as propargyl, dimethylpropargyl and the like; hydroxyalkyl of from 2 to about 5 carbon atoms r such as hydroxy-t-butyl and the like; 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 benzyl, phenethyl, 3,4-dimethoxyphenethyl and the like; and Ar is unsubstituted phenyl, or phenyl substituted with lower alkyl of from 1 to about 5 carbon atoms, fluoro, chloro, nitro, hydroxy, amino, acyloxy, wherein the acyl portion is alkanoyl of from 2 to about 5 carbon atoms, or benzoyl optionally substituted by halogen, alkoxy, alkyl vr hydroxy, or a group of the formula Rl~O~C~(cH2)n wherein R1 is lower alkyl of from 1 to about 5 carbon atomsr and n is an integer from 0 to about 5. In particularly preferred embodiments of the present : invention, R is selected from the group consisting of isopropyl, t-butyl, hydroxy-t-butyl, dimethylpropargyl, ~5 and 3,4-dimethoxyphenethyl, and Ar is unsubstituted phenyl or phenyl substituted with methyl, fluoro, chlorog nitro, hydroxy, amino, acyloxy such as acetoxy, isobutyryloxy, pivaloyloxy, benzoyloxy or 4-methoxybenzoyloxy.
The compounds described herein may be prepared by a number of synthetic methods, depending upon the particular structure desired.
Compounds of the invention may be advantageously prepared by either of the following two methods:

Method I:
O O
Il /~
Ar-C-Cl + HO-CH~-C~I-CH2 ~ ~

Ar-C-O-ClH 2-CH -C~ 2 O OH

Ar-C-O-CH~-CH-CH2~NHR; or Method II
O OH
/~ I
,~ Ho_cH2-cH-C~2 ~ B2N-R ~ HO-CH2-CH-CM2-NHR
O O OH

Ar-C-Cl Ar-C-O-CH2CH-CH2-NHR

The latter method is particularly preferred for compounds in which R is an ester-containing group.
The compounds of this invention are advantageously administered topically to the eye in the form of a solution, ointment, or solid insert such as is described in U.S. Patent No. 4,195,085. Formulations may contain 2S the active compound~ preferably, in the form of a soluble acid addition salt, in amounts ranging from about 0.01% to about 10% by wto, preferably, from about 0.5~ to about 5% by wt. Unit dosages of the active compound can range from about 0.001 to about 5.0 mg., preferably from about 0.05 to about 2.0 mg. The dosage administered to a patient will depend upon the patient's needs and the particular compounds employed.
Carriers used in the preparations of the present invention are preferably non-toxic pharmaceutical organic or inorganic compositions such as water;

~a mixtures of water and water-miscible solvents, such as lower alcohols; mineral oils; petroleum jellies; ethyl cellulose; polyvinylpyrrolidone and other conventional carriers. In addition, the pharmaceutical preparations may also contain additional components such as emulsifying, preserving, wetting and sterilizing agents.
These include polyethylene glycols 200, 300, 400 and 600, Carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, bacteriocidal components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in user thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering inyredients such as sodium chloride, sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate~
polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuceinate, monothioglycerol~ thiosorbitol, ethylenediamine tetracetic acid, and the like.
~0 Additionally, suitable ophthalmie vehicles can be used as carrier media for the present purpose ineluding conventional phosphate buffer vehicle systemsr isotonic borie acid vehicles, isotonic sodium chloride vehieles, isotonic sodium borate vehicles and the like.
2~ The method of treatment of this invention advantageously involves the topical administration of eye drops containing the active compound. Formulations for eye drops preferably include the active compound as a soluble aeid addition salt in a properly buffered, sterile, aqueous isotonie solution.
The compounds of the present invention are ester group-containing beta-blockers that have a selective, localized, beta-blocking ef~ect in the eye after topical administration. Such compounds are thought to be rapidly metabolized by plasma and/or liver esterases into inactive by-products, upon entering the systemic * Trade Mark J

~L-a-circulation. It has been discovered that these same compounds are relatively stable in ocular fluids, i.e., lacrimal fluids and aqueous humor. Consequently, such compounds are useful for the treatment of glaucoma or for lowering intraocular pressure since they remain stable when topically applied to the eye but rapidly metabolize when subsequently absorbed into the systemic circulat ion .
Some of the compounds break down in the aqueous humor more rapidly than others. Such compounds may advantageously be employed when only a temporary reduction in intraocular pressure is desired, say for diagnostic procedures. Longer-acting compounds are generally used for effecting longer-term reductions in intraocular pressure, such as is desired when treating chronic glaucoma. Thus, the method of the present invention provides a very useful therapeutic alternative for the treatment of glaucoma or for lowering intraocular pressure.
The ln vitro studies hereinafter described indicate that the compounds used in the method of the present invention will undergo different rates of enzymatic hydrolysis depending on their location withi~ the body (See Table I). For example, compound of Example III is completely hydrolyzed within 60 minutes in both dog blood and liver homogenate while only 19% hydrolyzed after one hour in aqueous humor, and only 51.9%
hydrolyzed after two hours. Compound of Example IV is less stable in aqueous humor, hydrolyzing 61.4% after one hour, 10Q% after two hours.
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 formula:

d~9~
_9_ ~ -C-O-CH2-CH-CH2-N-CH HCl 2,3 Epoxypropyl-2-chlorobenzoate A mixture containing 14.8g (0.2 mole) of glycidol, 150 ml of anhydrous ether, 169 (0.4 mole) of pyridine and 35.2g (0.2 mole) of 2-chlorobenzoyl chloride was stirred at room temperature for two hours. The mixture was filtered and the ether was evaporated to leave an oil. This oil was distilled to give a colorless oilD
The NMR and IR spectra were consistent with the assigned ; 15 structure.
[3-(Isopropylamino)-2-hydroxy]propyl 2-chlorobenzoate hydrochloride To 19 of the epoxide from the previous experiment were added 10g of isopropylamine. The resultant solution was refluxed for 16 hours and evaporated to dryness. The oily residue was chromatographed on a column (silica yel/EtOH:CH2Cl2 = 1.5:3.5) to yield the free amine product. The amine was converted to its HCl salt by addition o~ ethereal HCl. The amine salt 2~ was collected by filtration and recrystallized in 2-propanol to give white crystals: m.p. 129C. The NMR
and IR spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula C13H263NCl2-Example Ia This example describes an alternate synthesis of the compound of Example I.

A mixture of 37g (0~5 mole) of glycidol and 35.49 (0.6 mole) of isopropylamine was stirred at 25C.overnight. Excess isopropylamine was evaporated in vacuo and the mixture was distilled to give 53g of ___ product~ b.p~ 80C/0.1mm Hg. The NMR and IR spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula C6H152~1~
[3-(Isopropylamino) 2-hydroxy]propyl 2-chlorobenzoate hydrochlorid_ A sol~tion of 109 (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 t75 mmole) of 2-chlorobenzoyl chloride. The mixture was stirred at room temperature for two hours and 100 ml of water was added. The pyridine 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 12.59 (54%) of product: m.p. 129C.
Example II
-This example describes the synthesis of a compound of the formula:

25F- ~ -C-O-CH2-CH-CH~-N-CH HCl The experiment of Example la was repeated in all essential details to produce the above compound, except the reactant 4-fluorobenzoyl chloride was substituted for 2-chlorobenzoyl chloride. The compound was prepared as the acid addition salt. The compound was identified by NMR and IR spectroscopy, elemental analysis, and had a melting point of 139-140C.

E mple III_ This example describes the synthesis of a compound of the formula:
o OH CH3 -C-O-CH2-CH-CH2-N-C CH3 .HC1 The experiment of Example Ia was repeated in all essential details to produce the above compound, except the reactants t-butylamine and benzoyl chloride were substituted for isopropylamine and 2-chlorobenzoyl chloride, respectively. The compound was prepared as the acid addition salt. The compound was identified by NMR and IR spectroscopy, elemental analysis, and had a melting point of 105-106C.

Example IV
This example describes the synthesis of a compound of the formula:

-C-O-CH2-CH-CH2-N-C _ CH3 F

The experiment of Example Ia was repeated in all essential details to produce the above compound, except the reactants t-butylamine and 2-fluorobenzoyl chloride were substituted for isopropylamine and 2-chlorobenzoyl chloride, respectively. The compound was prepared as the free base. The compound was identified by NMR and IR spect:roscopy, elemental analysis, and had a melting point o 97.5-98C.

Examples V~-VIII
The en~ymatic hydrolysis rates of the compounds of Examples I-IV were examined in dog blood, liver homogenate, and aqueous humor. All of the compounds tested were synthesized in accordance with the previous examples. Acetonitrile was "HPLCI' grade. Distilled water was used to dissolve the compounds and 0.01 N HCl was used to dissolve compounds requiring an acidic pH
for dissolutioll.
Fresh aqueous humor was collected from eyes of dogs using a 23 gauge needle while fresh dog blood was collected into heparinized Vacutainer~ tubes. Fresh liver was homogenized in 0.9~ NaCl using a Potter-Elvehjem Teflon pestle and glass homogenizer making a 1~ 25% (W/V) homogenate.
A 0~5 ml aliquot of dog aqueous humor, blood, or liver homogenate was incubated with 12.5 u9 (0.5 ml) of beta-blocker in a Dubnoff shaking metabolic incubator at37C. for 60 and 120 minutes. Denatured tissue ~0 controls were prepared by adding 2.0 ml of acetonitrile into 005 ml of aqueous humor, blood, or liver homogenate to destroy esterase activities prior to addition of the beta-blockers. These controls were then incubated at 37C. for 120 minutes. After 60 and 120 minutes, ~he 2~ incubations were terminated by addition of 2 ml of acetonitrile and immediately mixed using a Vortex~ mixer to stop esterase activitiesO
All samples were centrifuged at 4000 RPM for 10 minutes to sediment denatured proteins. The resultant supernatants were transferred to WISP~ vials and analyzed by high pressure liquid chromatography. The hydrolysis of beta-blockers in aqueous humor, blood, and liver homogenate was determined by disappearance of the compounds. The extent of enzymatic hydrolysis in each tissue was determined by comparing the amount of each compound (absolute peak area~ recovered at each time * Trade l~ark ~3 point to the amount of each compound (absolute peak area) in denatured tissue control and a~ueous control samples.
All of the compounds examined were initially tested for chemical hydrolysis in 0.1 N potassium phosphate buffer, pH 7.40, and all were found to be stable for at least three hours (data not shown3.
Table 1 summarizes the results of these experiments. The extent of hydrolysis is expressed in terms of the amount of each compound recovered after the incubation period relative to the amount of each compound recovered in the denatured tissue control.
Most of the b _ blockers were hydrolyzed very rapidly (> 90~ in 120 minutes) when incubated with dog blood and liver homosenate. In contrast, all of the compounds tested were resistant to enzymatic hydrolysis by esterases in dog aqueous humor having hydrolysis rates of 19-61% in 60 minutes and 52-100% in 120 minutes.

Example IX
This example describes the synthesis of a compound of the formula:

2S CH3-O-c-cH2- ~ -C-O-CH2-CH-CH2-N-C~ ~Cl OH ~ CH3 2,3 Epoxypropyl 4-[Metho~ycarbonyl)methyl] benzoate A mixture containing 14.8g (0.2 mole) of glycidol, 150 ml o~ anhydrous ether, 169 (0.4 mole of pyridine and 30 43g l0.2 mole) of 4-[methoxycarbonyl)methyl]benzoyl chloride is stirred at room temperature for two hours.
The mixture is filt`ered and the ether evaporated to leave an oil. This oil is distilled to give a colorless oil.

.,, , , ~
, --lq--_-(Is~ ylamino)-2-hydroxy]propyl 4-[Me hoxycarbonyl) methyl~ benzoate To 1.6g of the epoxide from the previous experiment is added 10g of isopropylamine. The resultant solution is refluxed for 16 hours and evaporated to dryness. The oily residue is chromatographed on a column (silica gel/EtOH:CH2Cl2=1.5:3.5) to the freene product. The ami amine was converted to its HCl salt ddition of by a ethereal HCl. The amine salt was ted by 1Q collec filtration and recrystallized in nol to give 2-propa white crystals.
Example X
This example describes the synthesis of a compound of the formula:

HOCH2 ~ -C-O-CH2-lH-CH2-l-CH2 CH2 ~ -OCH3-(COo~)2

3-[N-[(4-methoxvbenzvl)oxycarbonyl]-N-(3,4-dimethoxyphenethyl)] amino-1,2-pro~ diol A mixture of 26g (0.102 mole) of 3-(3,4-dimethoxyphenethyl)amino 1,2-propanediol, 29g (0.345 mole) of sodium bicarbonate and 249 ~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-dimethoxyphenethyl)]amino]propyl 4-formylbenzoate 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 hyclrochloride in Example II. 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 dissolved in ethanol. The resulting solution was cooled to 0C. and sodium borohydride in a molar amount equal to the molar amount of the aldehyde was added.
The reaction mixture was stirred at 0C. for ten minu~es and excess hydride was destroyed by addition of wat~r.
The crude product was dissolved in ether-HCi and stirred at room temperature for two 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.
20 164-164.5~C. The NMR and IR spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula Exam~le XI
This example describes the synthesis of a compound of the following formula via Method I~
F
r-~ COOH
-COOCH2CHCH2NC(CH3)2C_CH COOH
OH H
ate A r;~ixture containiny 379 (0.5 mole) of glycidol, 500 ml of anhydrous ether, 500 ml of pyridine and 80g (0.5 mole) of o-fluoro-benzoyl chloride was stirred at 0C. for 1 hour and 25~C. for 2 hours. The mixture was filtered and the ethanol filtrate was washed with 100 ml of 5% HCl. Evaporation of the ether gave an oil which was distilled to give 69.5g (71%) of product/ b.p.
115C./0.5 mmHg. The NMR and IR spectra were consistent with the assigned structure.
3-(1,1-Dimethylpropargylamino ? -2-hydroxypropyl 2-Fluorobenzoate Oxalat_ To 9g (0.046 mole) of the epoxide from the previous experiment in 50 ml of THF was added 8.59 (0.092 mole) of 1,1-dimethylpropargylamine. The reaction mixture was refluxed for 16 hours and evaporated to dryness. The residue was dissolved in 100 ml of iPrOH and 6.5g (0.07 mole) of oxalic acid was added. Addition of 50 ml of ether into the iPrOH solution induced crystallization of the desired product, 3.84g (23%); m.p. 124-5~. The NMR
and IR spectra were consistent with the assigned structure and elemental analysis was consistent with the empirical formula C17H20NO7F.
Example XII
The example describes the synthesis of a compound of the following formula via Method II~
HO OH

2 5 H O~)--COOC H 2CH CH 2--21C ( CH 3 ~ 3 ~ HC l Ethyl 3,4-Dihydroxybenzoate A mixture which contained 43g ~0.28 mole) of 3,4-dihydroxybenzoic acid, 300 ml of ethanol and 0.5 ml of concentrated H2SO4 was refluxed for 48 hours. Water was trapped with 3A molecular sieves. The reaction mixture was evaporated to dryness in vacuor and partitioned between ether and 5% NaHCO3 solution. The ether layer was evaporated to give 399 ~69~) of solid;
m.p. 128-130C. The NMR and IR spectra were consistent with the assigned structure.

' - ~
~7X~33 3,4-Dibenæylox~enzoic Acid llo 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methyl ethyl ketone was added 105.5g (0.76 mole) of K2CO3 and 168.8g (0.76 mole) of benzyl bromide. The mixture was refluxed for 16 hours and filtered. Evaporation of the filtration gave an oil.
This oil was mixed with 40g of KOH, 350 ml of water and 350 ml of methanol and refluxed for 2.5 hours. The methanol was evaporated and the reaction mixture was acidified with concentrated HCl. The precipitate was filtered to give 101g (92~) of the desired product; m.p.
184-5C. The NMR and IR spectra were consistent with the assigned structure.
3-t-Butylamino-2-hydroxypropyl 3,4-dibenzyloxybenzoate To 20g (0.06 mole~ of the 3,4-dibenzyloxybenzoic acid in 200 ml of toluene was added 60g (0.33 mole) of thionyl chloride. The reaction mixture was evaporated to dryness in vacuo to give a solid; m.p. 85-86. The solid was dissolved in 100 ml of dry THF and added dropwise into a solution of 17.7g (0.06 mole) 3-~t-butylamino)-1,2-propanediol in 50 ml of pyridine and 50 ml of toluene. The reaction mixture was stirred for 1 hour at 25VC. and partitioned between ether and 5%
K2CO3 solution. The ether layer was evaporated to dryness to give 309 of solid.
3=tert-Butylamino-2-~ roxypropyl 3,4-Dihydroxybenzoate H drochloride Y
To 25g of the dibenzyloxybenzoate obtained from the previous experiment was added 50 ml of ether and acidi-fied with hydrogen chloride. The ether layer wasdecanted and the oily residue was dissolved in 200 ml of methanol with 2g of 10% Pd/catalyst~ The mixture was agitated for 16 hours under 50 psi of hydrogen. The catalyst was filtered and the filtrate was evaporated to dryness. The product was crystallized in iPrOH to give 14g (73~) of the product; m.p. 201-202. The NMR and IR
spectra were consistent with the assigned structure and elemental analysis was consistent with the empirical formula C14H22N5Cl-Examples XIII-XV
The experiment of Example XII was repeated in all essential detail to produce Examples XIII-XV described in Table 2 except that different benzyloxybenzoic acids were used to react with the 3-(t-butyl-amino)-1,2-propanediolsO Each of the compounds was identified by NMR, I~ and elemental analysis.

Examples XVI and XVII
The procedure ~or the preparation of 3-t-bu~ylamino-2-hydroxypropyl 3,4-dibenzyloxyben20ate in Example _II was repeated in all essential detail to produce Example XVII described in Table 2 except that 3,4-dipivaloyloxy benzoic acid was used to react with the 3-~tert-butylamino)-1,2 propanediol. The crude product of Example XVII was chromatographed on silica gel with 10~ EtOH in EtoAc to give Example XVII.
The NMR and IR spectra were consistent with the assigned structures. Comparative data relating to Examples XI to XVII are given in Table 2.

Example XVIII
The intraocular pressure lowering effect of the compounds described in Examples I-IV and IX~XVII are demonstrated in rabbits with normotensive eyes.
Sterile, isotonic saline solutions of each of the compounds prepared in procedures of Examples I-IV, IX-XVII are prepared by dissolving 10, 30 and 100 mg samples of each of the active compounds in 1 ml of saline to give 1%, 3% and 10% solutions with pH about 6.0-7Ø Free amines require one equivalent of HCl to effect dissolution.

~3~

The intraocular pressure lowering effect of each COll)pOUnd i5 determined by treatinc3 the eyes of healthy rabbits with the above solutions. Three rabbits are used to evaluate the effect of each drug concentration.
A standard dose of 50~1 of each drug solution is applied to one eye of each of the three rabbits.
Intraocular presure of both eyes is measured with a pressure tonograph or a Mackay-Marg Tonometer before drug administration and at 15, 30, 45, 60, 120, 180, 240, 300, 360, 420 and 480 minutes after dosing.
Control rabbits are treated similarly with sterile isotonic saline solution. Intraocular pressure lowering in the treated eyes is compared with the untreated eyes, with saline treated eyes and with predrug pressures.
All of the test compounds show intraocular pressure-lowering activity~

Example XIX
The experiment of Example XVIII is repeated in all essential details, except that rabbits which have corticosteroid induced ocular hypertension, as described by Bonomi, L., et al~, Glaucoma, Eds. R. Pittscrick, A~D.S~ Caldwell, Academic Press, New York, pp. 98-107 ~1980), are substituted or the normotensive rabbits.
Each of the test compounds exhibits intraocular pressure- lowering activity in this model.

--2()--TAB LE
ENZYMATIC HYDROLYSIS OF BETA BLOCKERS BY DOG BLOOD
L:[VER HOMOGENATE, AND AQUEOUS HUMOR

_ _ _ _ _ % HYDF~)LYZED

BLOOD LIVER AQUEOtlS HUMOR
CO~OUND
E~XAMPLE EX~MPLE 60 min 120 min 60 min 120 min V III 100 100 100 100 18.9 51.9 Vq II 100 100 100 100 21.9 61.8 10 VIII, Ia 77.4 90.8 90.1 96.1 39.2 71.6 VIIIrv 100 100 100 100 61.4 100 _ :~ lData at each time point are expressed relative to denatured tissue control.

OH
I
ArCOOCH2CHCH2-N-X
H

Add. Crystn.
Example Pr R Method Yield% Salt Solvent XI ~ -C(c~l3)2c-cH I 22.7(COOH)2 iPrOHo HO~ C(CH3)3 II73HCl iPrOH

XIII~ CH(CH3)2 II45(CCOH)2 Acetone HO ~ EtOAC
O
xrv ~ C(CH3)3 II58 ~ICl Acetone HO,~J EtOAC
HO
XVHO ~ C~CH3)3 II86 HCl Acetone . ~ HO
HO
XVI ~ C(CH3)3 II3 -(C~3)3C-CO
o XVII O C(CH3)3 II 21 - Oil (CH3)3C-C-O
(CH3)3C-C-O

Claims (12)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for making a compound of the formula:

or a pharmaceutically acceptable salt thereof which comprises reacting a first reactant of the formula:

with a second reactant selected from the group consisting of an epoxide of the formula:

or a secondary amine of the formula:

under substantially anhydrous conditions; and, when said sec-ond reactant is an epoxide, then further reacting the reaction product of the first and second reactants with a lower alkyl amine of the formula:

to give the final product; and optionally converting said fi-nal product to a pharmaceutically acceptable salt by reaction with an appropriate acid; wherein R is lower hydroxyalkyl or lower alkynyl, and Ar is unsubstituted phenyl or phenyl sub-stituted with lower alkyl of from 1 to about 5 carbon atoms, fluoro, chloro, nitro, hydroxy, amino, acyloxy, wherein the acyl portion is alkanoyl of from 2 to about 5 carbon atoms, or unsubstituted benzoyl or benzoyl substituted with halogen, lower alkoxy, lower alkyl, hydroxy or a group of the formula:

wherein R1 is lower alkyl of from 1 to about 5 carbon atoms and n is an integer from 0 to about 5; with the proviso that when Ar is phenyl substituted with 2 or 3 hydroxy groups, or phenyl substituted with acyloxy, wherein the acyl portion is alkanoyl of from 2 to about 5 carbon atoms, or benzoyl (op-tionally substituted by halogen, alkoxy, alkyl or hydroxy), R may optionally additionally be isopropyl, t-butyl or dime-thoxyphenethyl.

2. The process of claim 1, wherein R is lower hydroxy-alkyl of from 2 to about 7 carbon atoms or lower alkynyl of from 3 to about 10 carbon atoms, and Ar is unsubstituted phe-nyl or phenyl substituted with lower alkyl of from 1 to about 5 carbon atoms, fluoro, chloro, nitro, hydroxy, amino, acyl-oxy, wherein the acyl portion is alkanoyl of from 2 to about 5 carbon atoms, or unsubstituted benzoyl or benzoyl substituted with halogen, lower alkoxy, lower alkyl, hydroxy or a group of the formula:

wherein R1 is lower alkyl of from 1 to about 5 carbon atoms and n is an integer from 0 to about 5.

3. The process of claim 1, wherein R is lower hydroxy-alkyl of from 2 to about 5 carbon atoms or lower alkynyl of from 3 to about 5 carbon atoms, and Ar is unsubstituted phe-nyl or phenyl substituted with methyl, fluoro, chloro, nitro, hydroxy, amino, or acyloxy, wherein the acyl portion is alk-anoyl of from 2 to about 5 carbon atoms, or unsubstituted benzoyl or benzoyl substituted with halogen, lower alkyl or hydroxy.

4. The process of claim 1, wherein R is hydroxy-t-butyl or dimethylpropargyl, and Ar is phenyl, 2-chlorophenyl, 4-fluorophenyl, 2-fluorophenyl, hydroxyphenyl, dihydroxyphe-nyl, (pivaloyloxy)phenyl or (dipivaloyloxy)phenyl.

5. The process of claim 1, for making a compound of the formula:

wherein R is isopropyl, t-butyl, dimethylpropargyl, hydroxy-t-butyl or dimethoxyphenethyl, and n is 2 or 3.

6. The process of claim 1, for making a compound of the formula:

wherein R is isopropyl, t-butyl, dimethylpropargyl, hydroxy-t-butyl or dimethoxyphenethyl, and acyl is alkanoyl of from 2 to about 5 carbon atoms, or benzoyl, optionally substituted by halogen, alkoxy, alkyl or hydroxy.

7. A compound of the formula:

or a pharmaceutically acceptable salt thereof; wherein R is lower hydroxyalkyl or lower alkynyl, and Ar is unsubstituted phenyl or phenyl substituted with lower alkyl of from 1 to about 5 carbon atoms, fluoro, chloro, nitro, hydroxy, amino, acyloxy, wherein the acyl portion is alkanoyl of from 2 to about 5 carbon atoms, or unsubstituted benzoyl or benzoyl sub-stituted with halogen, lower alkoxy, lower alkyl, hydroxy or a group of the formula:

wherein R1 is lower alkyl of from 1 to about 5 carbon atoms, and n is an integer from 0 to about 5; with the proviso that when Ar is phenyl substituted with 2 or 3 hydroxy groups, or phenyl substituted with acyloxy, wherein the acyl portion is alkanoyl of from 2 to about 5 carbon atoms, or benzoyl (op-tionally substituted by halogen, alkoxy, alkyl or hydroxy), R may optionally additionally be isopropyl, t-butyl or dime-thoxyphenethyl.

8. A compound of the formula:

or a pharmaceutically acceptable salt thereof; wherein R is lower hydroxyalkyl of from 2 to about 7 carbon atoms or lower alkynyl of from 3 to about 10 carbon atoms, and Ar is unsub-stituted phenyl or phenyl substituted with lower alkyl of from 1 to about 5 carbon atoms, fluoro, chloro, nitro, hy-droxy, amino, acyloxy, wherein the acyl portion is alkanoyl of from 2 to about 5 carbon atoms, or unsubstituted benzoyl or benzoyl substituted with halogen, lower alkoxy, lower al-kyl, hydroxy or a group of the formula:

wherein R1 is lower alkyl of from 1 to about 5 carbon atoms, and n is an integer from 0 to about 5.

9. A compound of the formula:

or a pharmaceutically acceptable salt thereof; wherein R is lower hydroxyalkyl of from 2 to about 5 carbon atoms or lower alkynyl of from 3 to about 5 carbon atoms, and Ar is unsub-stituted phenyl or phenyl substituted with methyl, fluoro, chloro, nitro, hydroxy, amino, or acyloxy, wherein the acyl portion is alkanoyl of from 2 to about 5 carbon atoms, or unsubstituted benzoyl or benzoyl substituted with halogen, lower alkyl or hydroxy.

10. A compound of the formula:

or a pharmaceutically acceptable salt thereof; wherein R is hydroxy-t-butyl or dimethy]propargyl, and Ar is phenyl, 2-chlorophenyl, 4-fluorophenyl, 2-fluorophenyl, hydroxyphenyl, dihydroxyphenyl, (pivaloyloxy)phenyl or (dipivaloyloxy)phenyl.

11. A compound of the formula:

or a pharmaceutically acceptable salt thereof; wherein R is isopropyl, t-butyl, dimethylpropargyl, hydroxy-t-butyl or dimethoxyphenethyl, and n is 2 or 3.

12. A compound of the formula:

or a pharmaceutically acceptable salt thereof; wherein R is isopropyl, t-butyl, dimethylpropargyl, hydroxy-t-butyl or dimethoxyphenethyl, and acyl is alkanoyl of from 2 to about 5 carbon atoms, or benzoyl, optionally substituted by halogen, alkoxy, alkyl or hydroxy.