US3641152A - 3 4-dihydronaphthalenoneoxy-2-hydroxy-propylamines - Google Patents

Abstract

THE PRESENT INVENTION RELATES TO COMPOUNDS OF THE FORMULA:

1-(O=),2-R5,2-R6,(R1-N(-R2)-CH2-CH(-OH)-CH2-O-),R3,R4-

TETRALIN

WHEREIN R1 STANDS FOR HYDROGEN OR AN ALKYL GROUP AND R2 STANDS FOR AN ALKYL GROUP OF NOT MORE THAN 6 CARBON ATOMS, PREFERABLY BRANCHED SUCH AS ISOPROPYL, ISOBUTYL, SEC-BUTYL, TERT-BUTYL, AND THE LIKE; CYCLOALKYL GROUPS OF NOT MORE THAN 7 CARBON ATOMS, SUCH AS CYCLOPROPYL, CYCLOPROPYLMETHYL, CYCLOPENTYL, CYCLOPENTYLMETHYL, CYCLOHEXYL, CYCLOHEXYLMETHYL; LWER ALKENYL OR ARALKYL GROUPS, ANY OF WHICH MAY BE OPTIONALLY SUBSTITUTED; R3 AND R4 EACH STAND FOR HYDROGEN, OR HYDROXY; R5 AND R6 EACH STAND FOR HYDROGEN, ALKYL, OR ARALKYL; OR7 IN WHICH R7 IS LOWER ALKYL OR LOWER ALKENYL, ARALKYL SUCH AS BENZYL IN WHICH ARYL MAY BE OPTIONALLY SUBSTITUTED BY HALOGEN, NITRO, ETC.; HALOGENS SUCH AS F,CL,BR OR I; NITRO, AMINO OR ACYLAMINO, OR SULFONAMIDO; ALKYL SUCH AS METHYL AND CONTAINING NOT MORE THAN 6 CARBONS.

Description

United States Patent 3,641,152 3,4-DIHYDRONAPHTHALENONEOXY- Z-HYDROXY-PROPYLAMINES John Shave], Jr., Mendham, and Sheldon Farber, Livingston, N.J., assignors t0 Warner-Lambert Pharmaceutical Company, Morris Plains, NJ. No Drawing. Filed Sept. 23, 1%8, Ser. No. 761,857 Int. Cl. C07c 93/06 US. Cl. 260570.7 9 Claims ABSTRACT OF THE DISCLOSURE The present invention relates to compounds of the formula:

wherein R stands for hydrogen or an alkyl group and R stands for an alkyl group of not more than 6 carbon atoms, preferably branched such as isopropyl, isobutyl, sec-butyl, tert-butyl, and the like; cycloalkyl groups of not more than 7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl; lower alkenyl or aralkyl groups, any of which may be optionally substituted; R and R each stand for hydrogen, or hydroxy; R and R each stand for hydrogen, alkyl, or aralkyl; OR in which R is lower alkyl or lower alkenyl, aralkyl such as benzyl in which aryl may be optionally substituted by halogen, nitro, etc.; halogens such as F, Cl, Br or I; nitro, amino or acylamino, or sulfonamido; alkyl such as methyl and containing not more than 6 carbons.

The hydroxypropylamine side chain can be attached to either the 5, 6 or 7 position of the aromatic ring. It has been found that under the conditions used for the preparation of these compounds it is not possible to attach the side chain to the 8 position.

The compounds of this invention have fi-adrenergic blocking activity and are therefore useful in cases of angina pectoris, cardiac arrhythmia and other related cardiovascular ailments. Generally speaking, a dose of about 0.1 to about 1 mg./kg. of body weight of the animal being treated, administered either orally or by injection, is prescribed.

The present invention relates to compounds of the formula:

drogen, alkyl, or aralkyl; 0R in which R is lower alkyl or lower alkenyl, aralkyl such as benzyl in which aryl may be optionally substituted by halogen, nitro, etc.; halogens such as F, Cl, Br or I; nitro, amino or acylamino, or sulfonamido; alkyl such as methyl and containing not more than 6 carbons.

In the above definitions for R R R R R R and R lower alkyl includes 1 to 6 carbon atoms, lower alkenyl includes 2 to 6 carbon atoms, aryl includes both aromatic ring systems, such as phenyl, as well as heterocyclic ring systems such as pyridyl; acyl includes those radicals derived from lower alkanoic acids, such as acetic, propionic, butyric, and the like, as well as benzoic acid.

The compounds of this invention have been found to have B-adrenergic blocking activity both by injection and oral administration in mammals such as logs, cats, monkeys and the like. The ,B-adrenergic blocking activity of these compounds is determined by the administration of various doses of isoproterenol after dosage of the test animal with the compounds of this invention. It was found that the heart contractile force and heart rate response to isoproterenol is blocked by these compounds in varying degrees depending on the administered dose. As an example of the ,B-adrenergic blocking activity of these compounds, the compound 5 [3 (tert-butylamino) 2-hydroxypropoxyJtetralone hydrochloride was administered intravenously to anesthetized dogs at a dose of 6.7 g/kg. The dogs were then given 0.3 ,ugJkg. isoproterenol. This compound was capable of suppressing 50% of the iso proterenol effects on the dogs heart rate.

These compounds are useful where fl-adrenergic blocking agents, such as for example, propranolol, are indicated, for example in cases such as angina pectoris, cardiac arrythmia and other ischemic states.

The dosage regimen may be varied according to the age, sex, body weight and species of the mammal being treated and is in the range of about 0.1 to about 1 mg./kg. of body weight, either orally or by injection.

The present invention also incorporates within its scope pharmaceutically acceptable acid addition salts; for example, hydrochlorides, hydrobromides, phosphates, sulfates or salts derived from organic acids such as lactates, salicylates and the like.

The present invention also embraces the dor l-optical isomers or the racemic mixture, as well as their salts or derivatives described above.

It is recognized that certain derivatives of these compounds such as O-esters derived from acids of the type ZCOOH wherein Z stands for alkyl, alkenyl or aryl radical, optionally substituted of not more than 20 carbon atoms are also within the scope of this invention.

Additionally, the keto group at the 1-position forms derivatives with reagents such as hydroxylamine, semicarbazide, thiosemicarbazide, hydrazine and substituted hyrazines and accordingly such derivatives are included in the scope of this invention.

Suitable derivatives of the side chain such as the oxazolidine or oxazolidinone of the formula:

wherein R and R together represent 0 or separately R and R are hydrogens or alkyl groups such as methyl, etc., or aralkyl or phenyl optionally substituted, are also included.

A further feature of the aforesaid compounds is the provision of dosage forms suit-able for oral or parenteral administration. These pharmaceutical dosage forms suitable for oral administration may be in the form of tablets, capsules, aqueous or oily solutions and the like and suspensions which are readily compounded by methods known to the pharmaceutical art. For example, tablets may be formulated by admixture of the selected active ingredient with known pharamaceutical excipients, such as calcium phosphate, lactose, mannitol, and granulated with agents such as acacia or a gelatin solution and then compressed into tablets. These compounds may also be formulated to give a prolonged action in the animal body. Dosage forms suitable for parenteral administration may be formulated by dissolving or suspending the selected active ingredient in a parenterally acceptable vehicle such as sterile water, sterile saline, oil and the like.

In order to enhance the therapeutic spectrum, these compounds may also be combined with sedatives such as phenobarbital, analgesics such as aspirin, or cardiovascular agents, such as pentaerythritol tetranitrate, pentaerythritol trinitrate, etc.

The process for the preparation of these compounds is a further feature of the invention and consists of the interaction of a compound of the formula:

R OH

R4 wherein R R R R have the meanings stated above and limited to the cases where the OH is at the 5, 6 or 7 position, with XOH2CHCH2 wherein X=halogen such as C1, to give Generally speaking, the starting materials A and B or A and C are either refluxed together without solvent or reacted at room temperature in an alcoholic solution containing a slight excess (1.1 moles) of a base such as sodium hydroxide, potassium hydroxide or sodium methoxide to give intermediates corresponding to structures D and E. The intermediates D and E thus obtained are then treated for example by refluxing, with the appropriate amine of the Formula NI-IR R wherein R and R have the meanings stated above. As suitable solvents for these reactions, there may be mentioned, for example, lower aliphatic alcohols, such as methanol, ethanol and the like. The desired final products are recovered by methods well known to the art.

The starting phenol A is obtained by treating the corresponding ether which is commercially available with hydrogen bromide in acetic acid.

It has been found that under the conditions used for the preparation of these compounds it is not possible to attach the side chain to the 8 position.

According to the further features of this invention, we provide processes for the manufacture of the various derivatives described above including oxazolidines and semicarbazones. The procedures for the conversion are well known to the art and are readily apparent to those skilled in the art.

The following examples are included in order further to illustrate the invention. All temperatures are given in degrees centigrade.

EXAMPLE 1 CH3 +cH r Nail.

0x 0 cn o 2,2-dimethyl-6-methoxy-l-tetralone 71 g. of NaH powder (1.48 moles) 50% oil suspension is placed in a two liter three neck flask. The powder is triturated with two 300 ml. portions of petroleum ether and the supernatant decanted onto a piece of Dry Ice. Then 200 ml. of toluene followed by 200 ml. of DMF is added. Then 6-methoxy tetralone 60 g. (340 millimoles) is added rapidly in 250 ml. of DMF to which is then added 200 g. of CH I (1.41 moles). The temperature is maintained between 3237 by judicious use of ice 'bath. The reaction mixture becomes thick with a precipitate of NaI. When all the CH I is added the ice bath is removed and the heat of the reaction allowed to heat the reaction mixture up to 62 C. (a condenser is used at this point). The reaction mixture becomes slightly orange at this point and is cooled tod 53 C. at which point the temperature gradually sub- 51 e After stirring an hour the mixture is poured onto ice and the aqueous extracted twice with toluene and the toluene washed with water and dried (MgSO The toluene extracts are distilled under reduced pressure rapidly. A cut at '98-130/.2 is taken 58.6 grams and redistilled using a short Vigreux column and a middle cut taken at 113-119/ .25 1.5547.

Analysis.For C H 'O (percent): C, 76.44; H, 7.90; O, 15.67. Found (percent): C, 76.21; H, 7.74; O, 15.80.

EXAMPLE 2 CH3 m CH3 0 3 tat e CH O o 2,2-dimethyl-6-hydroxyl-tet'ralone EXAMPLE 3 5-(2,3-epoxypropyloxy)-l-tetralone A solution of 8.3 g. of NaOH in 36.5 ml. of water was diluted with 292 ml. of ethanol and then 28.5 g. of S-hydroxy-a-tetralone and 98 g. of epichlorohydrin were added. The mixture was stirred at room temperature for 16 hrs. and then left over the weekend. The solution was then evaporated and the residue was partitioned between 180 ml. of water and 250 ml. of chloroform. The separated aqueous layer was extracted with another 100 ml. of chloroform. The combined organic phases were washed twice with 100 ml. of water, dried and concentrated to give 41 g. of residue. This was dissolved in 280 ml. of ether and cooled, 4.5 g. of crystals were filtered off. The filtrate was stripped to give 34 g. and this was distilled at 136-144/ .08 mm. to give 261 g.

EXAMPLE 4 5- (2,3 -epoxypropyloxy) -8-methoxy-1-tetralone To a solution of 1.55 g. (38.8 millimoles) of sodium 'hydroxide in 50 ml. of methanol is added 6.76 g. (35.2 millimoles) of 5-hydroxy-8-methoxy-l-tetralone. After a solution has been obtained, epichlorohydrin. 32.4 g. (350 millimoles), is added and the resulting mixture is stirred at room temperature for 17 hours. After the reaction mixture has been evaporated in vacuo to give a liquid residue, the crude material is dissolved in 100 ml. of ether and that ethereal solution extracted with H O (3X 50 ml.). The ether solution is dried using anhydrous magnesium sulfate and then evaporated in vacuo to give an oily material which is further purified by fractional distillation; yield, 4.32 g. (50.1%), M.P. 85-88", B.P. 2002l1/ 0.6 mm.

EXAMPLE 5 cs cs n OH CH3 o-cn CH\ 0 CH2/ o-cn H 2 3 CH-OH 5, 8-dimethyl-7- (2,3 -epoxypropyloxy) l-tetralone A mixture of 40.0 g. (210 millimoles) of 5,8-dimethyl- 7-hydroxy-1-tetralone, 828 ml. (1.30 moles) of epichlorohydrin, 12.6 g. (232 millimoles) of sodium methoxide and 400 ml. of methanol is stirred at room temperature for 48 hours. The reaction mixture is evaporated in vacuo to a residual syrup which is dissolved in 250 ml. of ether and 250 ml. of l N sodium hydroxide. The ether phase is further Washed with H O (1X 200 ml.) and dried with anhydrous magnesium sulfate. Evaporation of the ether in vaeuo gives a liquid residue in excess of theoretical weight which is purified by distillation at reduced pressure; yield, 33.3 g. (60.7%), B.P. 183-185/0.35, M.P. 5660.

5- (2,3-epoxypropyloxy) -8-hydroxy-1-tetralone To a solution of 14.2 g. (354 millimoles) of sodium hydroxide in l l. of methanol is added 57.3 g. (322 millimoles) of 5,8-dihydroxy-l-tetralone and 298 g. (3.22 moles) of epichlorohydrin. The reaction mixture is allowed to stir at room temperature for 21 hours and then is evaporated in vacuo to give a crude oil which is dissolved in 800 ml. of ether. The ethereal solution is then washed with water (3 X 250 ml.) and dried with anhydrous magnesium sulfate. Evaporation of ether solution in vacuo gives a quantitative yield of 5-(2,3-epoxypropyloxy)-8-hydroxyl-tetralone crude product which is purified by distillation at reduced pressure; yield 52.6 g. (69.9% B.P. /0.06 mm., M.P. 6569.

EXAMPLE 7 7 -(3-cyclohexylamino-Z-hydroxypropyloxy)-8-hydroxyl-tetralone hydrochloride A mixture of 9.79 g. (41.9 millimoles) of 5-(2,3- epoxypropyloxy)-8-hydroxy-1-tetra1one, 50 ml. of cyclohexylamine and 50 m1. of methanol is refluxed for 1 hour. After evaporation of the reaction mixture has given the crude cyclohexylimino intermediate, the oily material is hydrolyzed to the 'free keto product in a mixture of concentrated hydrochloric acid and methanol (110 ml., 10% methanol) by heating at reflux temperature for 41 hours. Evaporation in vacuo of the reaction mixture gives the crude product as the hydrochloride salt which is purified by recrystallization from methanol; yield, 4.90 g. (31.5%), M.P. 193-195".

Analysis.For C H NO .HCl (percent): C, 61.70; H, 7.63; N, 3.79; Cl, 9.58. Found (percent): C, 61.84; H, 7.65; N, 3.58; Cl, 9.78.

A second preparation of the product yields analytical material with a M.P. 20l203.

EXAMPLE 8 5 3-tert-butylamino-2-hydroxypropyloxy 8-hydroxyl-tetralone hydrochloride A methanolic solution (22 ml.) of 5.50 g. (23.5 millimoles) of 5-(2,3-epoxypropyloxy)-8-hydroxy-1-tetralone and 22 ml. of tert butylamine is heated at reflux temperature for 1 hour and then evaporated in vacuo to give a crude liquid product. This material is converted to its hydrochloride salt and purified by recrystallization from methanol-ether giving the analytically pure sample; yield 4.53 g. (56.0%), M.P. 208-212".

AnaIysis.For C H NO .HCl (percent): C, 59.38; H, 7.62; N, 4.07; Cl, 10.31. Found (percent): C, 59.52; H, 7.79; N, 4.02; CI, 10.57.

EXAMPLE 9 OCH 8 5 3-cyclohexylamino-2-hydroxypropyloxy) -8 methoxyl-tetralone hydrochloride When a mixture of 10.0 g. (40.3 millimoles) of 5-(2,3- epoxypropyloxy)-8-methoxy-1-tetralone and 50 m1. of cyclohexylamine is heated at reflux temperature in 50 m1. of methanol, the crude cyclohexylimino intermediate is obtained when the volatile materials are removed from the reaction mixture. Upon refluxing a mixture of the imino analog in ml. of a methanol-6 N-hydrochloric acid mixture, and evaporation in vacuo, the crude hydrochloride salt of the expected product is obtained. The analytically pure, brown crystalline product is obtained by recrystallization from a propanol-ether mixture; yield, 8.10 g. (52.3%), M.P. 178-180".

Analysis.For CZOH2QNO4'HCI (percent): C, 62.57; H, 7.88; N, 3.65; Cl, 9.23. Found (percent): C, 62.46; H, 7.95; N, 3.60; C], 9.24, 9.52.

EXAMPLE 10 OCH Cl-l-CH 5 l-tert-butylamino-2-hydroxy-3-propyloxy)-8- methoxy-l-tetralone hydrochloride A solution containing 1.00 g. (4.03 millimoles) of 5- (2,3-epoxy-1-propyloxy)-8-methoxy-1-tetralone, 5 ml. of tert-butylamine and 5 m1. of methanol is heated at reflux for 1 hour. After the reaction has been evaporated in vacuo to a liquid residue, the crude product is converted to the hydrochloride salt; yield, 1.17 g. (89.9%), M.P. 185188 dec. Recrystallization of the crystalline material from methanol-ether gives the analytically pure sample; yield, 818 mg. (56.7%), M.P. 186- 190 dec.

Analysis.-For C H NO -HC1 (percent): C, 60.41; H, 7.89; N, 3.91; Cl, 9.91. Found (percent): C, 60.58; H, 7.87; N, 3.71; Cl, 9.80, 9.97.

EXAMPLE 11 CH3 CH3 091 (H'mz CH3 (I:H\O CH3 CHOH 7 -(3-cyclopropylamino-2-hydroxy-l-propyloxy) 5,8-dimethyl-1-tetralone hydrochloride A solution of 8.10 g. (32.9 millimoles) of 5,8-dimethyl- 7-(2,3-epoxy-1-propyloxy)-1-tetralone, and 18 ml. of cyclopropylamine in ml. of methanol is heated at reflux for 1 hour. Evaporation in vacuo of the reaction mixture gives a crude oily product which is purified as the hydrochloride salt from methanol-ether; yield, 6.18 g. (52.4%), M.P. 178-181.

Analysis.-For C H NO -HCl (percent): C, 63.61; H, 7.71; N, 4.12; Cl, 10.43. Found (percent): C, 63.75; H, 7.96; N, 3.88; Cl, 10.22, 10.25.

9 EXAMPLE 12 CH3 CH3 I 1111 O $11 1 CH3 k 3 CHOH ori -mt 5,8 -dim ethyl-7-( 3-cyclohexylamino-2-hydroxy- 1- propyloxyl-tetralone hydro chloride EXAMPLE 13 011 CH3 i 'O-fn Q 3 CH I f o 3 cHDl-l ca ua a (JEN-I3 cs 5,8-dimethyl-7-(3-isobutylamino-2-hydroxy-1- propyloxy)1-tetralone fumarate A mixture of 10.1 g. (39.5 millimoles) of distilled 5,8- dimethyl-7-(2,3-epoxypropyloxy)-l-tetralone, 100 ml. of isobutylamine, and 100 ml. of methanol is heated at a reflux temperature for 2 /2 hours. The reaction mixture is evaporated in vacuo and gives a residual oily material which is converted to the fumarate salt; yield, 7.77 g. (52.2%), M.P. 174178 dec. The tan solid is recrystallized from 2-propanol to give the analytically pure product; yield 5.90 g. (39.6%), M.P. 180183 dec.

Analysis-For C H NO /2C H O (percent): C, 66.82; H, 8.28; N, 3.71. Found (percent): C, 66.75; H,

EXAMPLE 14 o-ca (DH-CH O-CHQCHCHZ CH3 \0/ 2 cs C(Cll3)3 5,8-dimethyl-7-(3-tert-butylamino-2-hydroxy-1- propyloxy)-1-tetralone hydrochloride A reaction mixture containing 10.5 g. (42.7 millimoles) of 5,8 -dimethyl-7-(2,3-epoxypropyloxy)-1-tetralone, 30 ml. of tertbutylamine and 30 ml. of methanol, is refluxed for 2 /2 hours. Evaporation of the reaction mixture in vacuo gives a quantitative yield of liquid product which is converted to the hydrochloride salt; yield, 12.8 g. (84.2% M.P. 234-237 dec. The tan material is recrystallized from methanol-ether and the analytical sample is obtained; yield, 7.80 g. (51.3%), M.P. 236-240 dec.

10 Analysis.--For C H NO -HCl (percent): C, 64.12; H, 8.50; N, 3.94; CI, 9.96. Found (percent): C, 64.24; H, 8.48; N, 3.79; Cl, 10.18, 10.00.

EXAMPLE 15 CH3 cs no on I 3 OCHECHCHQ O-Cl-l Cl-lCli Nl-lCH CH3 CH3 CH3 5,8-dimethyl-7- (2-hydroxy-3 [2-propylamino]- propyloxy) -1-tetra1one fumarate A mixture of 8.48 g. (34.4 millimoles) of distilled 5,8- dimethyl-7-(2,3-epoxypropyloxy)-1-tetralone, 20 ml. of methanol and 30 ml. of isopropylamine is heated at reflux for 2 /2 hours. After the reaction mixture has been evaporated in vacuo a residual oil is obtained which is converted to the crude fumarate salt; yield, 8.96 g. (61.8% M.P. -95 dec. Recrystallization of the material from 2-propanol, containing 0.5% fumaric acid, gives the analytically pure product; yield, 6.32 g. (43.7% M.P. 155- 157 dec.

Analysis.For C13H27NO3'C4H4O4 (percent): C, 62.69; H, 7.41; N, 3.32. Found (percent): C, 63.02, 63.03; H, 7.53, 7.55; N, 3.05.

EXAMPLE 16 5- 3 -cyclohexy1amino-2-hydroxy- 1 -propyloxy) -1- tetralone hydrochloride A mixture of 9.63 g. (44.2 millimoles) of 5-(2,3-epoxyl-propyloxy)-1-tetralone, 30 ml. of cyclohexylamine and 30 ml. of, methanol is refluxed for 2 hours. After evaporation of the reaction mixture in vacuo has resulted in a crude oily material, the product is purified as its hydrochloride salt by recrystallization from methanol; 6.62 g., M.P. 265-270. The material is analyzed as the dihydrochloride salt of the l-cyclohexylimino derivative of the desired product.

Analysis.--For C H N O -2HCl (percent): C, 63.69; H, 8.54; N, 5.92; CI, 14.99. Found (percent): C, 63.92; H, 8.61; N, 6.02; Cl, 14.62, 14.89.

The imino intermediate is then heated at reflux in ml. of a mixture of methanol and 2 N HCl 1:1) for 1 hour. Evaporation in vacuo of this reaction mixture gave 6.14 g. (39.4% M.P. 218-225 of crude ketone product which is purified by recrystallization from methanol; yield, 4.65 g. (29.8%), M.P. ZZZ-223.

Analysis.-For C19H27NO3HCl (percent): C, 64.49; H, 7.98; N, 3.96; Cl, 10.02. Found (percent): C, 64.53; H, 7.87; N, 4.06; Cl, 9.83, 9.94.

EXAMPLE 17 5-{3- 1-hydroxy-2-methyl-2-propyl) amino] -2-hydroxy- 1-propyloxy}-l-tetralone hydrochloride A mixture of 5.18 g. (25.8 millimoles) of 5-(2,3-epoxyl-propyloxy)-1-tetralone, 11.5 g. (128 millimoles) of 2-amino-2-methylpropanol and 50 ml. of methanol is heated at reflux temperature for 1 hour. After the reaction mixture has been evaporated in vacuo giving the crude product in the form of an oil, the material heated for 1.5 hours in a mixture of 6 N hydrochloric acid and methanol (4:1) to remove any imino group which might have formed during the initial reaction. The reaction mixture is evaporated in vacuo to give the crude solid hydrochloride salt of the desired product. The analytically pure 1 1 sample is obtained in good yields by recrystallization from ethanol-ether; yield, 6.04 g. (68.7%), M.P. 180-183".

Analysis.For C H NO -HCl (percent): C, 59.38; H, 7.62; N, 4.07; Cl, 10.31. Found (percent): C, 59.31; H, 7.67; N, 4.11; Cl, 10.40, 10.42.

5 ,8-dimethy1-7- (3-cyclohexyl-5-oxazolidinyl) methoxy1-1-tetralone hydrochloride A mixture of 2.98 g. (8.59 millimoles) of 5,8-dimethyl 7 (3 cyclohexylamino 2 hydroxypropyloxy)-1- tetralone, 1.32 ml. of 40% aqueous formaldehyde, and 21 ml. of ethanol is heated at reflux for 1 /2 hours. After an additional 1.32 ml. of aqueous formaldehyde has been added to the mixture, the reaction is allowed to reflux for /2 additional hours. The reaction mixture is evaporated in vacuo to a residual oil which is dissolved in ethyl acetate (25 ml.) and dried with anhydrous magnesium sulfate. Evaporation of the ethyl acetate gives a crude oily product which is purified as the hydrochloride salt by recrystallization from methanol-ether; 2.23 g. (65.8%), M.P. 179184.

Analysis.--For C H NO .HCl (percent): C, 67.07; H, 8.19; N, 3.56; Cl. 9.00. Found (percent): C, 67.13; H, 8.30; N, 3.58; Cl, 8.75, 8.92.

5 (3-tert-butyl-5-oxazolidiny1)methoxy] l-tetralone hydrochloride An ethanolic solution (3.2 ml.) of 460 mg. (1.58 millimoles) of 5 (3 tert butylamino 2 hydroxypropyloxy)-1-tetralone, and 0.2 ml. of aqueous formaldehyde is heated at reflux for 3 /2 hours. An additional 0.2 ml. of the aqueous formaldehyde is added to the reaction mixture and refluxing is continued for a total of 21 hours. After evaporating the reaction mixture in vacuo to a residual oil which crystallized upon trituration with ether (HCl), the crude salt is recrystallized from methanolether to give the analytically pure material; yielded, 291 mg. (54.2%), M.P. 139-144 dec.

Analysis.For C H NO .HCl (percent): C, 63.61; H, 7.71; N, 4.12; CI, 10.43. Found (percent): C, 63.74; H, 7.99; N, 3.97; Cl, 10.36; 10.44.

12 EXAMPLE 2o o -CH2CH--CH2 o -c CH3 3 5- 3-tert-butyl-2-oxo-5-oxazo]idinyl) methoxy] -1-tetralone To a solution of 9.17 g. (31.6 millimoles) of 5-[3-(tertbutylamino) 2 hydroxypropyloxy] 1 tetralone in 50 ml. of dry tetrahydrofuran is added, at 0, 4.05 g. (40.0 millimoles) of triethylamine and 5.50 g.:(35.0 millimoles) of phenyl chloroformate and the resulting mixture is stirred at room temperature for 19 /2 hours. The resulting N-carbophenoxy intermediate is then heated with 2.05 g. (38.0 millimoles) of sodium methoxide in ml. of toluene for 22 hours at reflux temperature. After the reaction mixture has been extracted with 1 N NaOH (2X 50 ml.), the organic phase is dried with anhydrous magnesium sulfate and evaporated in vacuo to a crude solid material. Recrystallization of the product from carbon tetrachloride gives the white crystalline, analytically pure sample; yield, 6.65 g. (66.5%), M.P. 132-135".

Analysis.For C H NO (percent): C, 68.12; H, 7.31; N, 4.41. Found (percent): C, 67.98; H, 7.31; N, 4.54.

EXAMPLE 21 1- 0101-1 -CH-CH (OCH CH-CH Cl) 3-(tetralone-5-oxy)-1,2-epoxy-propane S-(tetralone-S-oxy)-1-chloro-2-hydr0xy-propane 13.8 g. of S-hydroxytetralone was dissolved in 75 ml. of epichlorohydrin and the solution was refluxed for 44 hours. The excess epichlorohydrin was removed in vacuo by heating on a water bath, the residue was distilled in a short path bantam-ware distillation apparatus, and 5 fractions were taken, B.P. 160-210/ .2 mm. All had strong ketone absorption and the last two also had strong hydroxyl absorption. From previous expts. it was determined that low hydroxyl absorption paralleled low chlorine analyses and high hydroxyl absorption paralleled high chlorine analyses; therefore it was deduced that a mixture of the epoxy compound and chlorohydrin was attained. These fractions were combined and used for reaction with amines.

5-[3-(tert-butylamino)-2-hydroxypropyloxy] tetralone 6 ml. of the mixture of epoxy and chlorohydrin compounds was dissolved in 100 ml. of 95% alcohol and 24 ml. of t-butylamine was added, and the mixture refluxed on the steam bath for 2 hours. The solvent was then stripped, the residue triturated with sat. sodium bicarbonate sol. and ether and 9.2 g. of the base was filtered off. This material was treated with alcoholic HCl and the precipitated NaCl was filtered 011?. The solution was stripped and the residue recrystallized from acetonitrile, M.P. 170-171 C.

Two recrystallizations from acetonitrile gave M.P. 226- 228 C.

on isopropylamine 5 [2-hydroxy-3- (isoproylamino propyloxy] tetralone 7 ml. of the mixture of epoxy and chlorohydrin compounds was dissolved in 100 ml. of 95% alcohol and 28 ml. of isopropylamine was added, and the solution was refluxed for 2 hours. The solvent was stripped otf and the residue triturated with sat. sodium bicarbonate soln. and extracted with ether which was washed with H 0 and dried. The calculated amount of alcoholic HCl was added to form the hydrochloride which was filtered off (4 g.). Two recrystallizations from alcohol gave the analytical sample, M.P. 1985-1995".

14 EXAMPLE 24 n! cs OCH Cl-I-Cl-l ruiur -ac1 3,4-dihydro-5- [2-hydroxy-3- (isopropylamine) propyloxy] 1 (2H)-naphthalenone hydrochloride 26.1 g. (.12 mole) of epoxide, 34.8 g. (.59 mole) isopropylamine in 121 m1. of 95 ethanol was refluxed for 40 min. The total was stripped to residue which Was crystallized from 240 ml. of cyclohexane to give 29.5 g., M.P. 77-80. This was dissolved in 135 ml. of chloroform and HCl gas was bubbled in until acidic. To this was added 25 ml. of ether and stirring continued until solids dropped out. An additional 240 ml. of ether was added and stirring continue for awhile, filtered, washed with ether and dried to give 33 g., M.P. 195-197.5. Recrystallization from 320 ml. of abs. EtOH gave the product, M.P. 196.5-198.

EXAMPLE 25 ocr-r -cgrr 5 3-tert-butylamino -2-hydroxypropyloxy] -3,4 dihydro- 1 (2H -naphthalenone 20.1 g. (0.918 mole) of epoxide, 33 g. tert butylamine in ml. of ethanol was refluxed for 40 min. The total was stripped to a residue which was crystallized from 90 ml. of cyclohexane to give 25.8 g., M.P. 84*86". This was dissolved in ml. of chloroform and HCl gas was bubbled in until acidic, cooled and diluted with 17 ml. ether. When crystals separated an additional 2.5 ml. of ether 'was added and stirring continued for awhile. The crystals were filtered, washed with ether and dried to give 28 g., M.P. 223-225". Recrystallization from abs. EtOH gave M.P. 2235-2255".

lIt is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing from the spirit of our invention.

Having described our invention, what we desire to secure by 'Letters Patent is:

1. A compound of the formula:

wherein R is hydrogen, R is lower alkyl of 1 to 6 carbon atoms; and R R R and R are hydrogen and the propanolamine side chain is substituted on the 5, 6 or 7 position of the aromatic ring; or its pharmaceutically acceptable acid addition salts.

2. A compound of the formula:

wherein R is hydrogen, R is branched lower alkyl of 3 to 5 carbon atoms and R R R and R are hydrogen, and the propanolamine side chain is substituted on the 5, 6 or 7 position of the aromatic nucleus; or its pharmaceutically acceptable acid addition salts.

3. A compound according to claim 1 wherein the compound of Formula I is 5-(3-tert-butylamino-2 hydroxypropyloxy)-8-hydroxy-1-tetralone.

4. A compound according to claim 1 wherein the compound of Formula I is 5-(1-tert-butylamino-2-hydroxy- 3-propyloxy)-8-methoxy-l-tetralone.

5. A compound according to claim 1 wherein the compound of Formula I is 5,8-dimethyl-7-(3-isobutylamino- Z-hydroxy-1-propyloxy)-1-tetralone.

6. A compound according to claim 1 wherein the compound of Formula I is 5,8-dimethy1-7-(3-terty-butylamino- Z-hydroxyl-propyloxy -1-tetra1one.

7. A compound according to claim 1 wherein the compound of Formula I is 5 ,8-dimethyl-7-(Z-hydroxy-BIZ- propylarninoJpropyloxy)-l-tetra1one.

8. A compound according to claim 1 wherein the compound of Formula I is 5-[3- (tert-butylamino)-2-hydroxypropyolxy] tetralone.

9. A compound according to claim 1 wherein the compound of Formula I is 5-[2-hydroxy-3-isopropylamino) propyolxy] tetralone.

References Cited UNITED STATES PATENTS 2,820,817 1/ 1958 Sam 260-570.7 X 3,415,873 12/1968 Stevens 260570.7 X

ROBERT V. HINES, Primary Examiner US. Cl. X.R.

260-295 K, 296 AB, 307 R, 307 C, 348 R, 476 R, 482 C, 486 R, 490, 501.18, 552 SC, 554, 556 AR, 558 R, 562 A, 566 R, 566 A, 566 13, 590, 612 D; 424330