CA1055528A - Alkylsulfonylphenoxypropanolamines - Google Patents

Abstract

ALKYLSULFONYLPHENOXYPROPANOLAMINES

Abstract of the Disclosure A new class of phenoxypropanolamine alkylsulfonyl derivatives and methods for their preparation are described. The new compounds possess cardioselective .beta.-adrenergic blocking properties and are useful in the treatment of heart diseases. l-(Isopropylamino)-3-[4-(methyl-sulfonyl)-m-tolyloxy]-2-propanol is representative of the compounds disclosed.

Description

1SSsz8 ALKYLSULFONYLPHENOXYPROPANOLAMINES

Background of the Invention ; This invention pertains to carbon compounds having drug and blo-affecting properties and in particular to alkylsulfonylphenoxypropyl-amine B-adrenergic blocking agents.
According to present belief, there are at least two sub-groups of ~-adrenergic receptors. Bl-Receptors are thought to mediate cardiac ; ~timulation and ~2-recePtors sre supposed to mediate relaxa~ion of smooth muscle responsible for vasodilating and bronchodilating effects;

refer to C. G. Dollery, et al., Clinical Pharmacology and Therapeu~icc, 10(6), 765-799 (1969); D. Jack, The Pharmaceutical Journal, 237-240 (August 29, 1970). Various derivatives of phenoxypropanolamines reportedly ~tl have ~-adrenergic blocking properties and there can be mentioned as representative of the state of the art, Netherlands Patent 69,0770C

(Derwent Basic No. 41,107) and Belgium Patent 762629 (Derwent Basic No.
55533S-B). The Netherlands patent, while generically disclosing pharmaceutical prepara~ions containing a variety of substituted (including alkylsulfonyl) phenoxypropanolamines, does not specifically disclose the lass of alkylsulfonylphenoxypropanolamines of the present invention. The Belgium patent 762629 describes a group of alkylsulfollylalkylplle-loxyprop.lno-lamine derivatives.
Summar~ of the Invention This invention relates generally to novel alkylsulfonylphenoxy-propylamines which possess cardioselective ~l-adrenergic blocking properties.
More particularly, the present invention provides a process for preparing a compound selected from the group consisting of alkylsulfonylphenoxyprop~nol-amines characterized by general structural Formula I and non-toxic pharmaceutically acceptable acid addition salts thereof.

~ O-CH2CHCHlNH-Rl R~ ~ R2 OH Formula I

R~
In Formula I, Rl represents a branched chain alkyl radical of 3 or 4 carbon atoms inclusive; phenoxyisopropyl or cycloalkyl of 3 to 6 carbon atoms inclusive; R2 represents hydrogen, lower alkyl of 1 to 4 carbon atoms inclusive; or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive; R3 represents hydrogen or lower alkyl of 1 to 4 carbon atoms inclusive; and R4 represents hydrogen or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive.
The compounds of Formula I are further defined in tllat one and only one of R2 or R4 is lower alkylsulfonyl.
Formulas Ia and Ib below and non-toxic pharmaceutically acceptable acid addition salts thereof further characterize the compounds of the invention.

~ O-CH C}3CH,~3-R~ ~ O-CH2CHCH,~3-R, R, Formula Ia Formula Ib _; ~ - 2 -105SS~

In Formulas Ia and Ib, R i8 lower alkyl, R, and R, are as defined above and only one of R, ls lower alkyl.
By the term "lower alkyl" as used herein, lt i8 meant that the carbon chain comprising thls group lnclute both straight and branched chsln carbon radlcals of 1 to 4 carbon atoms inclusive. Exemplary of these carbon chain radicals are methyl, ethyl, propyl, isopropyl, l-butyl, l-methylpropyl, 2-methylpropyl, and tert.-butyl. As used herein, the term "cycloalkyl" of 3 to 6 carbon atoms inclusive is intended to refer to any of the cycloalkyl radicals of 3 to 6 carbon atoms inclusive such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term "non-toxic pharmaceutically acceptable acid addition 6alts" as used herein refers to salts of compounds of Formula I formed with a variety of relatively non-toxic inorganic or organic acids such as acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzenesulfonic, p-toluenesulfonic, ant related acids. The acid addition salts of this lnvention are prepared in conventional manner by treating a solution or suspension of the free base in a reaction inert organic solvent with the desired acid and then recovering the salts which form by concentration under reduced pressure or by crystallization techniques.
Inasmuch as the compounds of general Formula I possess at least one asymmetric carbon atom, the present invention also includes all possible optically active forms and racemic mixture of the compounds. Resolution of the racemlc mixtures to provlde the optically active isomers of the compounds of Formula I i8 carried out by conventional methods relating to resolution of phenethanolamines, for example, by salt formation with an optically ~iiSS5~8 active acit such 88 d-tartaric, tibenzoyl-d-tart~ric, d-camphorsulfonic, d-mantelic, etc., followed by fractional crystallization.
According to the present inventlon, the alkylsulfonylphenoxyamines of Formula I are preparet by a process which comprises reactlng a phenol derivative of Formula II

R4 ~ R~ Formula II

wherein R2, R~ ant R4 have meanings hereinabove described with an epihalohytrin of Formula III

\ ~ Formula III

wherein X signifies halogen, prsferably chlorine or bromine, and condenslng the eplhalohytrln reaction product wlth an amine of Formula IV

H~N-Rl Formula IV

wherein Rl has the meanlng hereinabove tescribet; whereafter, if tesiret, the Formula I protuct in free base form is reactet with an acid in order to form an acit addition salt.
The Formula II alkylsulfonylphenols are obtainet by oxitizing the corresponding alkylthlophenols with hytrogen peroxide in accordance with standard procedures, refer to R. B. Wagner and H. D. Zook, Synthetlc Organlc Chemlstry, page 801 (1953 Wlley).
Slnce an epihalohydrin molecule of Formula III has two reactive positions, reaction with a phenol of Formula II may yield a mixture of Formulas V and VI reaction products wherein R2, R3, R4, and X are as 1~555;28 defined above.

~ OC~IlCHCH~-X , , ~ OCH2CH-CH2 R4 ~ R~ OH R~ ~ d R, R, Formula V Formula VI

During the further course of the process, however, the two possible intermediates of Formula V and Formula VI on condensation with a Formula IV amine yield the same flnal product of the present invention.
Consequently, it is not necessary to effect a separation of any mixtures of lntermediates of Formulas V and VI which may result from interaction of a Formula II phenol with a Formula III apihalohydrin.
If desired, the epihalohydrin reaction product may be taken up ln an inert solvent such as chloroform and shaken with excess concentrated hydrochloric acld to convert epoxides of Formula VI into the corresponding Formula V sulfonylphenoxyhalohydrin. Conversely, if desired, the halohydrins of Formula V may be converted to the corresponding Formula VI
epoxide ln conventional manner, e.g., by treatment with base according to the procedure of O. Stephenson, J. Chem. Soc., 1574 (1954).
~he interaction of Formula II phenols with Formula III epihalo-hydrins i9 carried out employing an excess of the epihalohydrin and a catalytic amount of a base catalyst such as N-benzylisopropylamine hydrochloride or pyrrolidine base. Other catalysts such as pyridine, piperidine, piperidine acetate, or piperidine hydrochloride are about equally effective.
Interaction of Formula II phenols with Formula III epihalohydrins can also be effected in basic med~um, e.g., sodium hydroxide, at ambient 1(3 SS528 temperatures aceording to the procedure of Y. M. Beasley, et al., J. Pharm.
Pharmacol., 10, 47-59 (1958).
Contensatlon of the epihalohydrin reaction produet with a Formula IV amine is carried out preferably in an organic solvent lnert under the reaction conditions, e.g., ethanol, toluene, dioxane.
The eondensation can also be effected in the absence of a reaction solvent by using exeess amine such as isopropylamine or tert.-butylamine.
Aecording to a further feature of the present invention, an alternate method for producing compounds of Formula I comprises reacting a Formula II phenol wlth a compound of Formula VII in alkaline medium CH,-/CH-CH,-N-R, Formula VII
~ R, to provide a compound of Formula VIII

OH
~ O-CH,CHCH,N-R, R ~ R~ R, Formula VIII
R, wherein R" R" R, and R4 have the same meaning as in Formula I and R~ stands for a hydrogenolysable radical such as benzyl or benzhydryl;
and converting said compound of Formula VIII to an alkylsulfonylphenoxy-amine of Formula I. Removal of the hydrogenolysable blocking group maybe effected by catalytic hydrogenation, for example by hydroger.ation in the presence of palladium-on-charcoal catalyst, in an inert solvent, e.g., ethanol or aqueou~ ethanol.
The co~pounds of Formula VII may be obtained according to known methods. For example, l-C(N-benzyl)isopropylamino]-2,3-epoxypropane is obtained by reactlon of N-benzylisopropylamine and epichlorohydrin in alkaline medium (e.g., aqueous potassium hydroxide) as described by L. Vllla, et al., Farmaco., Ed. Sci., 24(3), 349-357 (1969).
A preferred group of alkylsulfonylphenoxyamines of the preeent invention comprises compounds of Formula IX

~O-CH2CHCH~NH-Rl ~ OH Formula IX
R"
R, wherein specific values for Rl, R~ and R4 are those defined above.
Speclflc alkylsulfonylphenoxyamlnes whlch fall wlthln the scope of the preferred group are, for example, l-(lsopropylamlno-3-C4-(methylsulfonyl)-m-tolyloxy]-2-propanol, 1-(tert.-butylamlno)-3-C4-(methylsulfonyl)-m-tolyloxy]-2-propanol, l-(lsopropylamino)-3-[4-(methylsulfonyl)phenoxy]-2-propanol, 1- ~ ,--butylamino)-3-C4-(methylsulfonyl)phenoxy]-2-propanol.
A stlll further preferred group of compound~ of Formula rx are those whereln R, i9 limited to isopropyl and tert.-butyl radicals and R4 is limited to the methylsulfonyl radical.
Cardioselective ~l-adrenergic blocking activity of the

2~ compounds of the present lnvention can be assessed ln standsrd in vitro pharmacologlcal tests systems such as the spontaneously beating rabbit atrlal preparation and the guinea pig tracheal preparation. The following Table 1, which compares potency ratios of 1-(isopropylamino)-3-C4-(methyl-sulfonyl)-3-tolyloxy]-2-propanol hydrochloride and the clinically useful B-adrenergic receptor antagonist propranolol, is illustrative of the cartlac selectivlty of the compounds of the present invention.
Table 1.

A Comparison of ~-Adrenergic Receptor Antagonlst Molar Potencies Determined in Rabbit Atrial and Guinea Pi~ Tracheal Preparations Cardio-selectivity Potency Ratio Potency Ratio Ratio:
ComPound Atria Trachea Atria/Trachea 10 Propranolol l-(Isopropylamino)-3-C4-(methylsulfonyl)-3-tolyloxy]-2-propanol hydrochloride 0~37 0.01 37 A preferred compound of this invention, l-(isopropylamino)-3-[4-(methylsulfonyl)-3-tolyloxy]-2-propanol hydrochloride, inhibits lncreased contractile force and heart rate in the anesthetized dog $ntuced by a standard challenge dose of 0.2 mcg./kg. (intravenous) of lsoproterenol when intravenously administered at an ED,o of 0.71 mg./kg.
body weight and 2.02 mg./kg. body weight respectively.
Another important property of the compounds of the inventlon is that they have llttle toxicity in mammals. With l-(isopropylamino)-3-C4-(methylsulfonyl)-m-tolyloxy]-2-propanol hydrochloride, for lnstance, oral LD,o values in the mouse and rat are 1504 and 1792 mg./kg. body weight respectively; the intraper~toneal LD,o value ~n the mouse is 339 mg./kg. body weight.
Substances of the present invention represented by Formula I
are novel compositions useful in the prophylaxis and treatment of heart diseases such as angina pectoris, cardiac arrhythmia~, cardiovascular anxiety (neurasthenia) and hypertension. The Formula I alkylsulfonyl-phenoxyamines are partlcularly of value in the treatment of heart dlseases 1055S2~3 because they possess selective ~-adrenergic blocking activlty. Compounds exhiblting thls selective action preferentially block cardiac inotropic and chronotropic actlon of catecholamines such as epinephrine and ~soproterenol without greatly affecting the ~l-adrenergic receptors in bronchial and vascular muscle.
For the purpose of exerting a cardioselective ~l-adrenergic blocking effect, the alkylsulfonylphenoxypropanolamines of Formula I
may be administered orally or parenterally to a mammal in doses ranging from 0.05 mg. per kilogram body weight to 20 mg. per kilogram body weight.
Preferably, the compoundQ of the inventlon are administered to a mammal ln an effective amount sufficient to reduce the inotropic, chronotropic effect of ~-adrenergic agonists withouth appreciably affecting the ~-adrenergic receptors in the mammalian smooth muscle tissue.
The alkylsulfonylphenoxypropanolamines of Formula I may be compoundet and formulated with organic or inorganic solid materials or liqulds which are pharmaceutically acceptable carriers to provide pharmaceutical compositlons of unit dosage form suitable for administration to mammals. Phsrmaceutlcal compositions may take the form of tablets, capsules, powder, granules,~suspensions, solutions and the like. Suitable pharmaceutical carriers comprise both solids and liquids such as corn starch, lactose, calcium phosphate, stearic acid, polyethyleneglycol, water, sesame seed oil, peanut oil, propyleneglycol, and so for.h.
Standard formulating procedures are employed to prepare the pharmaceutical compositions.
The following examples illustrate the preparation of specific compounds having ~-adrenergic cardioselective blocking activlty and should not be construed as a limitation of the invention.

The nuclear magnetic spectral data reported herein includes the chemical shift6 (~) In parts per million, the multiplicity for that shift ~ncludlng the coupling constant (Hz = J value) when appropriate, and the relative area under the curve for each chemical shift which corresponds to the number of protons. Multiplicity symbols are: s, single;; bs, broad slnglet; d, doublet; and m, multiplet. Tetramethylsilane was used as the internal reference.
Example 1 (a) A mixture of 4-(methylsulfonyl)-m-cresol (18.6 g., 0.1 mole), epichlorohydrin (60 g., 0.65 mole) and 0.6 g. of pyrrolidine iB heated on a steam bath for 12 hr. Excess epichlorohydrin is removed under reduced pressure, the resulting chlorohydrin derivative taken up in 50 ml. of absolute ethanol and filtered through diatomaceous earth.
Isopropylamine (50 g., 0.85 mole) and 0.1 g. of potassium iodide are added to the ethanol filtrat~ of the epichlorohydrin derivative and the mixture iB refluxed for 18 hr. and filtered. Concentration of the filtrate under reduced pressure affords a residue which is taken up in 70 ml. of lN
hydrochloric acid and 300 ml. of absolute ethanol. Distillables are removed under reduced pressure and the resulting residue stirred with ether to provide solid crude product. Crystallization of the crude product from butanone-methanol and again from 95% ethanol-ether, affords l-(ISOPROPYIA~IINO)-3{ 4-(~THYLSUnFONYL)-m-TOLYLOXY]-2-PROP~NOL HYDROCHLORIDE, m.p. 177.0-179.0C. (corr.) i3 a 62~ overall yield. A sample, m.p.
176.0-178.0C. (corr), analyzed as follows.
Analysis. Calcd. for C,4H~,NO4-HCl: C, 49.77; H, 7.16;
N, 4.15. Found: C, 49.72; H, 7.16; N, 4.08.
Nuclear Magnetic Res~nance, DMSO-d 6, ~ (ppm): 1.28 Cd, 6.5 Hz, 6H~; 2.58 [s, 3H]; 3.11 [s, 3H]; 3.13 [m, 3H]; 4.11 ~m, 3H]; 7.01 Cm, 2H];
7-77 Cd, 9.2 Hz, lH~; 8.9 [bs, 2H].

(b) A modificatlon of the procedure for preparing l-(isopropyl-amino)-3-C4-(methyl3ulfonyl)-m-tolyloxy~-2-propanol employing aqueous sodlum hydroxlde as the reaction medium follows. Epichlorohydrin (37 g., 0.4 mole) is atded portionwise in 5 min. to a solution of 4-(methylsulfonyl)-m-cresol (0.2 mole) and sodium hydroxide (13 g., 0.32 mole) in 250 ml. of water at 30C. Stirring is continued for 24 hr. and the final pH of the solution is 8-8.5. The reaction mixture extracted with two 250 ml. portions of chloroform, the chloroform extract dried over sodium carbonate, filtered and the filtrate concentrated under reduced pressure provides the crude epichlorohydrin terivative. The epichlorohydrin derivative is taken up ln 150 ml. of ethanol and trested with lsopropylamlne (17 g., 0.286 mole) ln 20 ml. of water. After stirring for 10 min., the mixture i8 refluxed for 4 hr. and distillables removed under reduced pressure. The residue taken up in ethanol and acidified with ethanolic hydrogen chloride affords 1-(ISOPROPYI~IINO)-3-L4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL HYDROCHLORIDE.
(c) A further modi~icatlon of the procedure for preparing l-(lsopropylamlno)-3-C4-(methylsulfonyl)-m-tolyloxy]-2-propanol employing an eplhalohydrin derivatlve of Formula VII containing a hydrogenolyæiable blocking group f ollows; l-C (N-Benzyl)isopropylamino]-2,3-epoxypropane 18 reacted wlth 4-(methylsulfonyl)-m-cresol sodium salt in ethanol to provlde l-C(N-benzyl)isopropylamino]-3- 4-(methylsulfonyl)-m-tolyloxy -2-propanol.
The reaction mixture is filtered, acidified with ethanolic hydrogen chloride and the benzyl bloc~ing group removed by catalytic hydrogenation employing palladium-on-charcoal catalyst. The catalyst ls collected and the filtrate concentrated to provide l-(ISOPROPYL-AMINO)-3-C4-(METHYLSULFONYL)-m-TOLYLOXY~-2-PROPANOL HYDROCHLORIDE.

1~5552~

Example 2.- Reac~ion of the chlorohydrin derivative of 4-(methylsulfonyl)-m-cresol with tert.-butylamine according to the procedure of Example 1 ta) affords l-(tert.-BU m ~YINO)-3-C4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL HYDROCHLORIDE, m.p. 175.0-176.0C. (resolidifying and remelting at 197.0C.)(corr.)., from acetonitrile.
Analysis. Calcd. for C,5H~NO4S-HCl: C, 51.20; H, 7.45; N, 3.98.
Found: C, 50.99; H, 7.72; N, 4.20.
Nuclear Magnetic Resonance, DMSO-d6, ~(ppm): 1.31 Cs, 9H];
2.59 [8, 3H]; 3.02 [m, 2H]; 3.11 C8, 3H]; 4.10 Cm, 3H]; 6.97 Cm, 2H];
7-75 Cd, 9.5 Hz, lH]; 8.7 Cbs, 2H].
Example 3.- Reaction of the chlorohydrin derivative of 4-(metnylsulfonyl)phenol with isopropylamine according to the procedure of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-C4-(METHYLSULFONYL)PHENOXY]-2-PROPANOL HYDROCHLORIDE, m.p. 193.0-195.0C., from ethanol.
Analysis. Calcd. for Cl,H2,NO4S-HCl: C, 48.22; H, 6.85;
N, 4.32. Found: C, 48.00; H, 7.02; N, 4.25.
Nuclear Magnetic Resonance, DMSO-d6, ~(ppm): 1.28 Cd, 6.5 Hz, 6H]; 3.12 Cm, 3H]; 3.14 Cs, 3H]; 4.13 Cm, 3H]; 5.91 Cd, 4.2 Hz, lH];
7.13 Cm, 2H]; 7.80 Cm, 2H]; 8.9 Cbs, 2H].
~ -- Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)-o-cresol with isopropylamine sccording to the proc~dure of Example 1 (a) affords 1-(ISOPROPYLAMINO~-3-C4-(METHYLSULFONYL)-o-TOLYLOXY]-2-PRQPANOL as the free base, m.p. 118.0-120.0C., from butanone.
Analysis. Calcd. for Cl4H~9NO4S: C, 55.79; H, 7.69; N, 4.65.
Found: C, 56.00; H, 7.68; N, 4.42.
~uclear Magnetic Resonance, CDCl" ~(ppm): 1.10 Cd, 6.4 Hz, 6H]; 2.27 Cs, 3H~; 2.50 [bs, 2H]; 2.85 [m, 3H]; 2.99 [s, 3H]; 4.11 Cm, 3H];
6.86 Cd, 9.3 Hz, lH~; 7.65 Cm, 2P.].

Example 5.- Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)phenol with tert.-butylamine according to the procedure of Example 1 (a) affords 1-(tert.-BUTYLAMINO)-3-[4-(METHYLSULFONYL)PHENOXY]-2-PROPANOL, m.p. 221.0 - 223.0C. (corr.) Analysis. Calcd. for C H NO S.HCl: C, 49.77; H, 7.16; N, 4.15.

Found: C, 50.10; H, 7.33; N, 4.00.
Example 6.- Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)-m-cresol with cyclopropylamine according to the procedure of Example l (a) affords l-(CYCLOPROPYLAMINO)-3-[4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL, m.p. 144.5 - 147.5C. (corr.) Analysis- Calcd. for C14H21NO4S.HCl: C, 50.07; H, 6.60; N, 4.17.
Found: C, 50.23; H, 6.76; N, 4.02.
Example 7.- Reaction of chlorohydrin derivative of 4-(methylsulfonyl)-m-cresol with phenoxyisopropylamine according to the procedure of Example 1 (a) affords 1-(PHENOXYISOPROPYLAMINO)-3-[4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL, m.p. 143.5 - 147.5C. (corr.) Analysis- Calcd- for C20H27NO5S: C, 61.05; H, 6.92; N, 3.56.
Found: C, 61.12; H, 7.14; N. 3.32.
Example 8.- Reaction of the chlorohydrin derivative of 2-(methylsulfonyl)phenol with isopropylamine according to the procedure of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-[2-(METHYLSULFONYL)PHENOXY]-2-PROPANOL, m.p. 187.5 - 189.5C. (corr.) Analysis- Calcd- for C13H21NO4S.HCl: C, 48.22; H, 6.85; N, 4.32.
Found: C, 48.19; H, 7.05; N, 4.37.
Example 9.- Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)-m-cresol with cyclopentylamine according to the procedure of Example 1 (a) affords 1-(CYCLOPENTYLAMINO)-3-[4-(METHYLSULFONYL)-m-TOLYLOXY]-2-PROPANOL HYDROCHLORIDE, m.p. 183.0 - 185.0C. (corr.) Analysis. Calcd. for Cl6H25NO4S HCl: C, 52.81; H, 7.20; N, 3.85-Found: C, 53.04; H, 7.37; N, 3.69.
Nuclear Magnetic Resonance, DMSO-d6, ~(ppm); 1.70 [m, 9H]; 2.58 [s, 3H]; 3,12 [s, 3H]; 3.15 [m, 3H]; 4.10 Lm, 3H]; 5.84 [bs, lH]; 6.94 [m, 2H]; 7.76 [d, 9.5 Hz, lH]; 9.0 [bs, 2H].
Example 10.- Reaction of the chlorohydrin derivative of 4-(sec.-butylsulfonyl)phenol with isopropylamine according to the ..~

procedure of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-[4-(sec.-BUTYLSULFONYL)P}IENOXY]-2-PROPANOL.
Example 11.- Reaction of the chlorohydrin derivative of 4-(lsopropylsulfonyl)-m-cresol with tert.-butylamine according to the procedure of Example 1 (a) affords 1-(tert.-BUTYLAMINO)-3-C4-(ISOPROPYLSULFONYL)-m-TOLYLOXY~-2-PROPANOL.
Example 12.- Reaction of the chlorohydrin derivative of 4-(methylsulfonyl)-3-isopropylphenol with isopropylamine according to the procedure of Example 1 (a) affords 1-(ISOPROPYLAMINO)-3-C4-(METHYLSULFONYL)-3-ISOPROPYLPHENOXY]-2-PROPANOL.

Claims (20)

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

1. A process for preparing a compound selected from the group consisting of an alkylsulfonylphenoxypropanolamine of the formula Formula I
and a non-toxic pharmaceutically acceptable acid addition salt thereof wherein R1 is a branched chain alkyl group of 3 or 4 carbon atoms inclusive, phenoxyisopropyl or cycloalkyl of 3 to 6 carbon atoms inclusive;
R2 is hydrogen, lower alkyl of 1 to 4 carbon atoms inclusive or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive;
R3 is hydrogen or lower alkyl of 1 to 4 carbon atoms inclusive; and R4 is hydrogen or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive;
wherein one and only one of R2 and R4 is lower alkylsulfonyl which comprises reacting a phenol derivative of Formula II

Formula II
wherein R2, R3, and R4 have meanings hereinabove described with an epihalohydrin of Formula III

Formula III

wherein X signififies halogen, preferably chlorine or bromine, and con-densing the epihalohydrin reaction product with an amine of Formula IV

H2N-R1 Formula IV

wherein R1 has the meaning hereinabove described; whereafter, if desired, the Formula I product in free base form is reacted with an acid in order to form an acid addition salt.

2. The compound selected from the group consisting of an alkylsulfonylphenoxypropanolamine of the formula Formula I
and a non-toxic pharmaceutically acceptable acid addition salt thereof wherein R1 is a branched chain alkyl group of 3 or 4 carbon atoms inclusive, phenoxyisopropyl or cycloalkyl of 3 to 6 carbon atoms inclusive;

R2 is hydrogen, lower alkyl of 1 to 4 carbon atoms inclusive or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive;
R3 is hydrogen or lower alkvl of 1 to 4 carbon atoms inclusive; and R4 is hydrogen or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive;
wherein one and only one of R2 and R4 is lower alkylsulfonyl, whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.

3. The process of preparing 1-(isopropylamino)-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the reaction product of 9-(methylsulfonyl)-m-cresol and epichlorohydrin is reacted with isopropylamine.

4. The compound 1-(isopropylamino)-3-[4-(methyl-sulfonyl)-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 3 or an obvious chemical equivalent thereof.

5. The process of preparing l-(tert.-butylamino)-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the reaction product of 4-(methylsulfonyl)-m-cresol and epichlorohydrin is reacted with tert.-butylamine.

6. The compound l-(tert.-butylamino)-3-[4-(methylsulfonyl)-m-tolyloxyl-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 5 or an obvious chemical equivalent thereof.

7. The process of preparing l-(isopropylamino)-3-[4-(methylsulfonyl)phenoxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the reaction product of 4-(methylsulfonyl)phenol and epichlorohydrin is reacted with isopropylamine.

8. The compound 1-(isopropylamino)-3-[4-(methylsulfonyl)-phenoxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 7 or an obvious chemical equivalent thereof.

9. The process of preparing 1-(isopropylamino)-3-[4-(methylsulfonyl)-o-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the reaction product of 4-(methylsulfonyl)-o-cresol and epichlorohydrin is reacted with isopropylamine.

10. The compound l-(isopropylamino)-3-L4-(methylsulfonyl)-o-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 9 or an obvious chemical equivalent thereof.

11. The process of preparing l-(tert.-butylamino)-3-[4-(methylsulfonyl)phenoxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the reaction product of 4-(methylsulfonyl)phenol and epichlorohydrin is reacted with tert.-butylamine.

12. The compound l-(tert.-butylamino)-3-[4-(methylsulfonyl)-phenoxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 11 or an obvious chemical equivalent thereof.

13. The process of preparing l-(cyclopropylamino)-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the reaction product of 4-(methylsulfonyl)-m-cresol and epichlorohydrin is reacted with cyclopropylamine.

14. The compound l-(cyclopropylamino)-3-[4-methylsulfonyl)-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 13 or an obvious chemical equivalent thereof.

15. The process of preparing l-(phenoxyisopropyl-amino)-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the reaction product of 4-(methylsulfonyl)-m-cresol and epichlorohydrin is reacted with phenoxyisopropylamine.

16. The compound l-(phenoxyisopropylamino)-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 15 or an obvious chemical equivalent thereof.

17. The process of preparing l-(isopropylamino)-3-[2-(methylsulfonyl)phenoxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the product of 2-(methylsulfonyl)phenol and epichlorohydrin is reacted withisopropylamine.

18. The compound l-(isopropylamino)-3-[2-(methylsulfonyl)-phenoxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 17 or an obvious chemical equivalent thereof.

19. The process of preparing l-(cyclopentylamino)-3-[4-(methylsulfonyl)-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof in accordance with the process of claim 1 wherein the product of 4-(methylsulfonyl)-m-cresol and epichlorohydrin is reacted with cyclopentylamine.

20. The compound l-(cyclopentylamino)-3-[4-(methylsulfonyl-m-tolyloxy]-2-propanol and a non-toxic pharmaceutically acceptable acid addition salt thereof whenever prepared by the process of claim 19 or an obvious chemical equivalent thereof.