DE2513806A1 - ALKYLSULFONYLPHENOXYPROPANOLAMINES, THE METHOD OF MANUFACTURING THEM AND THE AGENTS CONTAINING THEY - Google Patents

Description

PATENTANWÄLTE Ζ, U j O Ö U U PROF. DR. DR. J. REITSTÖTTER DR.-ING. WOLFRAM BÜNTE DR. WERNER KINZEBACH

D-βΟΟΟ MUNICH 4O. BAUERSTRASee 22 · FERNRUF (Οββ) 37 6β 83 ■ TELEX B2IS2OB ISAR D POSTAL ADDRESS: D-BOOO MÜNCHEN 43. POST BOX 78Ο

March 27, 1975

^, r η BRISTOL-MYERS COMPANY

M / l6 c-38

345, Park Avenue, New York, N.Y. 10022, USA

Alkylsulfonylphenoxypropanolamines,

Process for their manufacture

and agents containing them

The invention relates to new alkylsulfonylphenoxypropanolamines that exhibit cardioselective β-adrenergic blocking properties and that are useful in the treatment of Heart disease are useful. The present invention also relates to a process for the preparation of these compounds, as well as drugs containing these compounds.

It is currently believed that there are at least two subsets of ß-adrenergic receptors: ß-receptors, of believed to mediate cardiac stimulation and ß -receptors believed to mediate Mediate relaxation of the smooth muscles responsible for the vasodilatory and bronchodilatory effects (See, CG. Dollery, et al, Clinical Pharmacology and Therapeutics, lo (6), 765-799 (1969) and D. Jack, the Pharmaceutical Journal, 237-24o (Aug 29, 197o)). According to Numerous derivatives of phenoxypropanolamines have been reported in the prior art to be β-adrenergic Olockicrung properties (see, for example, the Dutch patent specification 69o77oo and the Belgian patent specification 762629). The aforementioned Dutch Pa-

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Tentschrift does disclose pharmaceuticals in general She discloses preparations containing a variety of substituted (including alkylsulfonyl) phenoxypropano! Amines but not specifically the class of the present invention Alkylsulfonylphenoxypropanolamines. It also describes the Belgian patent only describes a group of alkylsulfonylalkylphenoxypropanolamine derivatives.

The present invention provides alkylsulfonylphenoxypropanolamine linkages of formula I.

0-CH ₀ CHCH ₀ NH-R. OH

(I)

or pharmaceutically acceptable acid addition salts thereof, wherein R. is a branched chain alkyl radical having 3 or 4 carbon atoms (such as isopropyl, sec «-butyl, isobutyl and tert-butyl), phenoxyisopropyl or cycloalkyl having 3 to 6 carbon atoms inclusive; R _{0 represents} hydrogen, lower alkyl of 1 to 4 carbon atoms inclusive, or lower alkylsulfonyl of 1 to 4 carbon atoms inclusive; R is hydrogen or lower alkyl of 1 to 4 carbon atoms inclusive; R. for hydrogen or lower alkylsulphonyl with 1 to 4 carbon atoms inclusive and in which only one and only one of the radicals R ₀ and R. has the meaning of lower alkylsulphonyl.

Preferred compounds according to the invention include those those by the formulas

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0-CH _n CHCH ₀ NH-R. (S ^ ^ YO-CH ₀ CHCH ₀ NH-R ₁

OH VA ° ^H

SO ₂ R

(Ia) and (Ib)

R SO ₂ R

are characterized in which R stands for lower alkyl, R and R have the above meanings and in which only one of the radicals R_ is lower alkyl, and pharmaceutically acceptable acid addition salts thereof.

Another preferred group of those according to the invention Alkylsulfonylphenoxypropanolamines are among compounds of the Formula IX

0-CH ₀ CHCH ₀ NH-R ₁

OH

(IX)

wherein R ₁ , R, and R have the meanings given above. Examples of compounds of Formula IX include:

1- (Isopropylamino) -3- (.4- (methyl sulfonyl) -m-tolyloxyj -2-propanol, 1- ( tert -butylamino) -3 - [^ - (methylsulfonyl) -m-tolyloxyl r. 2- propanol,

1- (Isopropylamino) -3-14- (methylsulfonyl) phenoxy] -2-propanol

1- ( tert -Butylamino) -3- [4- (methylsulfonyl) phenoxy! -2-propanol.

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A further preferred group - / on compounds dor formula IX include those in which R ^ is isopropyl or tert-butyl and R is methyl.

The E-ssr.-ifi "ziieari.trss Alk-cl ^t! Used here includes straight-chain and branched Eoia.lsns ^- isffrssts rui'i 1 to ¹ L of carbon atoms including, bsispisls -.- rsise Msifoyl, ethyl, propyl, isopropyl, 1-butyl, 1-methylpropyl, 2-methylpropyl and tert-butyl Examples of cycloalkyl groups having 3 to 6 carbon atoms including cyclopropyl, cyclobuyl, cyclopentyl and cyclohexyl.

The term “pharmaceutically acceptable acid addition salt ^{11 used here} relates to salts of compounds of the formula I which have been formed with an inorganic or organic acid such as, for example, acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, cinnamic acid, fumaric acid, sulfuric acid acid, phosphoric acid, hydrochloric acid, hydrobromic hydriodic _5, suif asnin acid, suif onic acids, such as example-j

j wise methanesulphonic acid, besizolsulphonic acid, p-toluenesulphonic acid

acid and VBr ¹ WaIldt en acids. The acid addition salts according to the invention are prepared in a customary manner, for example by treating a solution or suspension

the free base in a reaction, organic solvents -inerten with the desired acid and subsequent extraction \ of the forming salt by concentration under reduced pressure, or by crystallization techniques, manufactured! represents.

As far as the compounds of the formula I are at least one asymmetric Having carbon atom embraces the present invention all possible optically active forms and racemic

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Mixtures of these compounds. The resolution of the racemic mixtures to create the optically active isomers of the compounds of the formula I is carried out by customary methods that are used in the separation of phenathanolamines, for example by salt formation with an optically active acid, such as d-tartaric acid, dibenzoyl-d-tartaric acid, d-camphorsulfonic acid, d-mandelic acid and the like can be applied, followed by fractional crystallization.

The present invention also provides a process for the preparation of an alkylsulfonylphenoxypropanolamine compound of formula I.

0-CK ₀ CHCH ₀ NH-R.

OH

or a pharmaceutically acceptable acid addition salt thereof, wherein;

R. represents a branched chain alkyl radical of 3 or k carbon atoms, phenoxyisopropyl or cycloalkyl of 3 to 6 carbon atoms inclusive;

R _{2 represents} hydrogen, lower alkyl of 1 to k carbon atoms inclusive, or · represents lower alkylsulfonyl of 1 to 4 carbon atoms inclusive;

R is hydrogen or lower alkyl of 1 to k carbon atoms inclusive;

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R. hydrogen or lower alkylsulfonyl with 1 to Represents carbon atoms including and-

a mza. only one of the radicals R _c . vnid R _fr for lower alkyl stilf onr / Z, sees _;

dadurcii. jjrekennz excimer- _s VAT

(&} a piiai-ol of the formula

W5) * ^: i: "i. _c: !: "and. E ^, the g

one verbiiidunj !? of the formula Χ

^ iI -.————>;; _A i. "Via" / *

wherein X is halogen or a group of the formula

-N- R ₁ R-

stands where R, has the above meanings and M ₁ = a hydrogenolysable Es εν. (ντύ.% Bsiizyl or · licnzhydryl} represents _v

~ ft C © / i <i / f f; I PV

W ^ V ί · Wv H- '. Ϊ i 'J: Λ; /;

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j (b) subsequently, -if X is halogen (preferably chlorine or ί Bromine) stands, the reaction product of step (a) with a

, Amine of formula IV

^H 2 ^N " ^R 1

wherein R _{1 has} the above meanings, condensed,

or, when X is said group of the formula

- NO,

^l 5

1
R.

means,

hydrogenating the reaction product of step (a) to remove the hydrogenolyzable blocking group, and

(c) if an acid addition salt of the compound of the formula I is desired, reacting the free base form of the compound of the formula I, which was prepared in step (b) , with a suitable acid.

Alkylsulfonylphenols of the formula II are obtained by reacting the corresponding alkylthiophenols with hydrogen peroxide using standard methods; see RB Wagner and HD Zook, Synthetic Organic Chemistry, page 8ol (1953 Wiley).

Since the epxhalohydrate molecule of the formula III has two reactive positions, the reaction with a phenol of the formula II can lead to a mixture of reaction products of the formulas V and VI, in which R, R, R and X have the above meanings.

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-Q-

OCH ₂ CHCH ₂ -X

OH
^R 2

(V)

OCH ₀ CH-CH ₀

² \ / O

(VI)

During the further course of the process, however, the two possible intermediates of the formulas V and VI provide the condensation with an amine of the formula IV is the same according to the invention End product. Consequently, it is not necessary to separate any mixtures of intermediates of the formulas V and VI to carry out the reaction of a phenol of the formula II with an epihalohydrin derive from formula III.

If desired, the epihalohydrin reaction product in an inert solvent such as chloroform and with an excess of concentrated hydrochloric acid be shaken to convert epoxies of the formula VI into the corresponding sulfonylphenoxyhalohydrin of the formula V. convict. Conversely, if desired, the halohydrins of the formula V can be used in a customary manner, for example by treatment with base according to the method of 0. Stephenson, J. Chem. Soc, 157 ^ (195 ^ t) into the corresponding epoxide of formula VI be convicted.

The reaction of the phenols of the formula II with the epihalohydrins of the formula III is carried out by adding an excess of the epihalohydrin and a catalytic amount of a base catalyst such as N-benzylisopropylamine hydrochloride or pyrrolidine base is used. Other catalysts, like Pyridine, piperidine, piperidine acetate or piperidine hydrochloride are about equally effective.

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j The reaction of the phenols of the formula II with the epihalohydrins: of the formula III can also be carried out in a basic medium, for example

wise sodium hydroxide and at ambient temperature according to the method of YM BeaSley, et al., J. Pharm. Pharmacol., Io,! ^l i7-59 (1958).

The condensation of the epihalohydrin reaction product with an amine of Formula IV is preferably carried out in an organic Solvent carried out which is inert under the reaction conditions, for example ethanol, toluene, dioxane. the Condensation can also occur in the absence of a reaction solvent be carried out using excess amine such as isopropylamine or tert-butylamine.

When the compound of the formula II is reacted with a compound of the formula III in which X is the group of the formula

NR ₁ CH ₀ -CH-CH ₀ -NR.

R_ »i.e. 0 R- (VII)

5 5

represents, a reaction product of the formula VIII is obtained

OH

0-CH ₀ CHCH ₀ NO.

5 (VIII), ^R 3

wherein R ₁₁ R ₀ , R ₁ R, and R_ the above meanings be-ι d. 3 * j

sit.

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The compound of formula VIII is by hydrogenation in a
Compound of formula I converted. The removal of the hydrogenolysable blocking group R _r can be carried out by catalytic
Hydrogenation, for example by hydrogenation in the presence
a palladium-on-charcoal catalyst, in an inert
Solvents, for example ethanol or aqueous ethanol,
take place.

ι The compounds of formula VII according to known Me- \ methods can be obtained. For example, 1-f (N-benzyl) -i isopropylamino-2,3-epoxypropane is obtained by reacting N-benzyl-isopropylamine and epichlorohydrin in an alkaline medium (for example aqueous sodium hydroxide), as described by L. Villa , et al., Farmaco., Ed. Sci., 24 (3), 349-357 (1969) j. j

The cardioselective ß .. adrenergic blocking activity
the compounds according to the invention can by customary in
vitro pharmacological test systems such as the spontaneously beat- | de Eanincheii atrial preparation and the guinea pig ί trachea preparation. The following
Table 1, which compares the efficacy ratios of 1-clsopropylamino) -3- [4- (methylsulfonyl) ^ -tolyloxyJ ^ -propanol hydrochloride and the clinically useful β-adrenergic receptor antagonist propranolol, explains the
Cardiac selectivity of the compounds according to the invention "

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Table 1

Comparison of the molar effectiveness of the ß-adrenergic receptor antagonist, determined in rabbit auricle and guinea pig trachea preparations

Efficacy Efficacy Cardioselecti-j relation relation vity relation-j

Connection to the auricle of the trachea: auricle | court / trachea j

Propranolol 11 1

l- (isopropylamino) -

3- Qi- (methylsulfonyl) -

3-tolyloxyi ~ 2-propa-

nol hydrochloride o, 37 o, ol 37

1- (Isopropylamino) -3-p- (methylsulfonyl) -3-tolyloxyj-2-propanol hydrochloride, a preferred compound of the invention, inhibits those in the anesthetized dog a standard dose of 0.2 µg / kg (intravenous) isoproterenol induced, increased contractile force and heart rate when at an ED _ of 0.71 mg / kg body weight or 2.02 mg / kg body weight is administered intravenously.

Another important property of the compounds according to the invention is that they have low toxicity in mammals. So with l- (Isopropylamino) 3-Ml- (methylsulfonyl) -m-tolyloxy] -2-propanol hydrochloride for example the oral LD values in mice and rats or 1792 mg / kg body weight. The intraperitoneal LD value in the mouse is 339 mg / kg body weight.

The compounds according to the invention represented by the formula I. are in the prophylaxis and treatment of heart diseases such as angina pectoris, cardiac arrhythmia,

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cardiovascular anxiety (neurasthenia) and hypertension, valuable. The alkylsulfonylphenoxyamines of the formula I. are particularly valuable in the treatment of cardiovascular diseases, since they have selective IL adrenergic blocking activity. Compounds that have this selective effect preferably block the inotropic and chronotropic cardiac action of catecholamines, such as epinephrine and isoproterenol, without the ß-adrenergic receptors in the bronchial and vascular muscles being particularly impaired would.

The alkylsulfonylphenoxypropanolamines can be used to exercise a cardioselective ß-adrenergic blocking effect of formula I orally or parenterally to a mammal in doses of 0.05 mg to 20 mg per kilogram of body weight administered. Preferably, the invention

: if compounds are administered in an amount to a mammal, which is sufficient to reduce the inotropic, chronotropic effect of ß-adrenergic agonists without the ß-adrenergic receptors in smooth muscle tissue in mammals are noticeably impaired.

The alkylsulfonylphenoxypropanolamines of Formula I can be 'compounded with pharmaceutically acceptable carriers and '' formulated to create pharmaceutical compositions,

namely in unit dosage form for administration ^site: suitable monitoring to mammals. Pharmaceutical means! can be in the form of tablets, capsules, powders, granules, suspensions, solutions and the like. Suitable pharmaceutical carriers can be organic or inorganic; They include solids and liquids such as corn starch, lactose, calcium phosphate, stearic acid, polyethylene glycol, water, sesame seed oil, peanut oil, propylene

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glycol, etc. Usual formulation methods can be used to prepare the pharmaceutical agents.

The following examples serve to explain the preparation of compounds according to the invention; these examples are not intended to limit the present invention.

The nuclear magnetic ones given in the following examples Spectral data includes the chemical shift (S) in parts per million, the multiplicity of this shift, including the coupling constant (Hz = J value) if displayed and the relative area under the curve for each chemical shift, which corresponds to the number of protons. The symbols of multiplicity are: s = singlet; bs = broad singlet; d = doublet; m = multiplet. as tetramethylsilane was used internally.

example 1

(a) A mixture of 18.6 g (0.1 mol) ^ - (methylsulfonyl) -m-cresol, 60 g (0.65 mol) of epichlorohydrin and 0.6 g of pyrrolidine are heated on a steam bath for 12 hours. Excess Epichlorohydrin is removed under reduced pressure.

The chlorohydrin derivative obtained is taken in 50 ml of absolute Ethanol and filtered through diatomaceous earth. 50 g (0.85 mol) of isopropylamine and 0.1 g of potassium iodide are used for the Ethanol filtrate of the epichlorohydrin derivative added. the The resulting mixture is refluxed for 18 hours and then filtered. Concentrate the filtrate to reduce Pressure gives a residue which is taken up in 70 ml of hydrochloric acid and 300 ml of absolute ethanol. Distillable materials are removed under reduced pressure and the residue obtained is stirred with ether,

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to obtain a raw, solid product. Crystallization of the crude product from butanone / methanol followed by recrystallization from 95 % ethanol / ether, gives 1- (isopropylamino) -3- £ 4- (niethylsulfonyl) -m-tolyloxyj -2-propanol hydrochloride with melting point 177 »ο - 179, o ° C (corrected) in an overall yield of 62 %. A sample with a melting point of 176.0 - 178.0 ⁰ C (corrected) provides the following analysis:

analysis

NO ^ -HCl

calculated: found:

49.77 49.72

H 7.16

7.16

4.15 4, o8

Nuclear magnetic resonance; DMSO-d, -, $ (ppm):

1.28 [d, 6.5 Hz, 6hJ; 2.58 [s, 3h]; 3.11 C ^s 1 3h] ; 3.13 fm, 3hJ; 4.11 £ m, 3h] ; 7, oil [m, 2hJ ; 7.77 [d, 9.2 Hz, J; 8.9 [bs, 2h].

(b) Using aqueous sodium hydroxide as the reaction medium, the 1- (isopropylamino) -3- [4- (methylsulfonyl) -m-tolyloxyj-2-propanol is prepared according to the following modified procedure: 37 g (0.4 mol) epichlorohydrin are added in portions in the course of 5 minutes to a solution of 37-2 g (0.2 mol) of 4- (methylsulfonyl) -mcresol and 13 g (0.32 mol) of sodium hydroxide in 250 ml of water at 3o C. The mixture is stirred for a further 24 hours. The final pH of the solution is 8 to 8 _$ 5 · The Reaktionsmis'chung is extracted with two 25o ml portions of chloroform. The chloroform extract is dried over sodium carbonate and filtered. The filtrate is concentrated under reduced pressure to obtain the crude epichlorohydrin extract.

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The epichlorohydrin derivative is taken up in 150 ml of ethanol and treated with 17 g (0.286 mol) of isopropylamine in 20 ml of water. After ten minutes of stirring, the mixture becomes 4 hours refluxed and distillable materials removed under reduced pressure. The received The residue is taken up in ethanol and acidified with ethanolic hydrogen chloride, l- (isopropylamino) -3- [4- (methylsulfonyl) -m-tolyloxyJ -2-propanol hydrochloride is obtained.

(c) Another modification of the process for the preparation of l- (isopropylamino) -3- | _4- (methylsulfonyl) -m-tolyloxyj 2-propanol, wherein an epihalohydrin derivative of the formula VII, which contains a liydrogenolxsbaren blocking group, is used is as follows: 1-JJN-benzyl) isopropylaminoj-2,3-epoxypropane is used with ^ - (methylsulfonyl) -m-cresol sodium salt in ethanol to give 1-J_ (N-benzyl) isopropyl- j aminoJ-3-4- (methylsulfonyl) -m-tolyloxy-2-propanol.

The reaction mixture is filtered, acidified with ethanolic hydrogen chloride and the benzyl blocking S group is removed by catalytic hydrogenation using a palladium-on-charcoal catalyst. The catalyst is collected and the filtrate is concentrated to give 1- (isopropylamino) -3- 0t- (methylsulfonyl) -m-tolyloxyJ-2-propanol hydrochloride receives.

Example 2

Reaction of the chlorohydrin derivative of 4- (methylsulfonyl) -mcresol with tert-butylamine according to the method of

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Game 1 (a) yields the 1- (tert-butylamino) -3- (methylsulfonyl) -m-tolyloxyj 2-propanol hydrochloride during crystallization from acetonetrile with a melting point of 175 »ο - 176, ο C (Resolidification and repeated melting at 197, ο C) (corrected).

Analysis:

calculated: found:

51.2o 7.45 3.98

Nuclear Magnetic Resonance, DMSO-dg, <$ (ppm):

1.31 £ s, 9h]; 2.59 [s, 3η] ϊ 3.02 £ m _f 2hJ; 3, f J 4, Io [m, 3H]; 6.97 [a, 2hJ; 7.75 [d, 9.5 Hz, in]; 8.7 [bs, 2]

Example 3

Reaction of the chlorohydrin derivative of 4- (methylsulfonyl) phenol with isopropylamine according to the procedure of Example 1 (a) gives the l- (isopropylamino) -3- on crystallization from ethanol | 4- (methylsulfonyl) phenoxy-2-propanol hydrochloride with melting point 193, o - 195, o ° C

Analysis: C ₁₃ H ₂₁ NO ₄ S-HC, L: C H 85 N 32 calculated: 48.22 6, o2 4th 25th found: 48, oo 7, 4,

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Nuclear Magnetic Resonance, DMSO-d ^, ό (ppm):

1.28 [d, 6.5 Hz, 6II]; 3.12 [m, 3hJ; 3.14 fs, 5h]; [m, 3hJ; 5.91 [d, 4.2 Hz, 1h]; 7.13 [m, 2H]; 7.8o [m, 2H]; 8.9 [bs, 2h].

Example 4

Reaction of the chlorohydrin derivative of 4- (methylsulfonyl) -ocresol with isopropylamine according to the procedure of Example 1 (a) gives H when crystallized from butano 1- (Isopropylamino) -3- [4- (methylsulfonyl) -o-tolyloxy-2-propanol in the form of the free base with melting point Il8, o -

12ο, ο C. S ₄ ^ V = C. H 69 4th N Analysis: calculated: 55.79 7, 68 4th , 65 found: 56.00 7, , 42

Nuclear Magnetic Resonance, CDCl, <£ Cppm):

l, lo [d, 6.4 Hz, 6h]; 2.27 [s, 3h]; 2.5o [bs, 2h]; 2.85

, 3hJ; 2.99 fs, 3h]; 4.11 [m, 3h]; 6.86 [d, 9.3Hz, 1h]; 7.65 [m, 2H].

Example 5

Reaction of the chlorohydrin derivative of 4- (methylsulfonyl) phenol with tert-butylamine according to the procedure of Example 1 (a) gives the l- (tert-butylamino) -3- [4- (methy! sulfonyl) -

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phenoxy j-2-propanol in the form of the free base. The free base is in the hydrochloride salt with melting point 221, ο 223, o ° C convicted ..

Analysis: C ₁₄ H NO ₄ -HCl: CHN

calculated: 49.77.7.16 4.15 found: 50, lo 7.33 4.00

Example 6

Reaction of the chlorohydrin derivative of 4- (methylsulfonyl) -mcresol with cyclopropylamine according to the procedure of Example 1 (a) yields 1- (cyclopropylamino) -3- [4-methylsulfonyl) -m-tolyloxy-2-propanol in the form of the free base. The free base is converted into the hydrochloride salt with a melting point 144.5-147.5 ° C transferred.

50 , 07 6th , 60 4th , 17th 50 , 23 6th , 76 4th , 02

Analysis: C.-H N0./HC1: CHN

calculated:
found:

Example 7

Reaction of the chlorohydrin derivative of 4- (methylsulfonyl) -mcresol with phenoxyisopropylamine according to the procedure of Example 1 (a) gives the 1- (PhenoxyisopropylaEixno) -5- [4- (methylsulfonyl) -m-1οlylos.yj ~ 2-propanol in the form of the free Base. The free base is converted into the hydrochloride salt with a melting point of 143.5-147.5 ° C.

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Analysis: C ₀ ^ H NO S: CHN

calculated: 6l, o5 6.92 3.56 found: 6l, 12 7.1 ^ 3.32

Example 8

Reaction of the chlorohydrin derivative of 2- (methylsulfonyl) -phenol with isopropylamine according to the procedure of Example 1 (a) gives the 1- (isopropylamino) -3- [_ 2- (methylsulfonylhenoxyJ-2-propanol in the form of the free base free T3aso is in the hydrochloride salt melting at 187.5 - 189.5 ^o C transferred.

Analysis: C ₁ H ₂₁ NO ₄ S-HCl:

HN

48 , 22 6th , 85 k , 32 kS , 19th 7th , 05 k , 37

calculated found:

Example 9

Reaction of the chlorohydrin derivative of 4- (methylsulfpnyl) -mcresol with cyclopentylamine according to the procedure of Example 1 (a) gives the 1- (cyclopentylamino) -3- [4- (methylsulfonyl) -m-tolyloxyl-2-propanol hydrochloride with melting point 183.0 - 185.0 ⁰ C (corrected).

Analysis: C ₁ ^ H ₀ -NO-S-HCl: CHN

calculated: 52.81 7.2o 3.85

found: 53, ok 7.37 '3.69

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Nuclear magnetic resonance, DMSO-d, -, ό (ppm): l, 7o [m, 9hJ; 2.58 [s, 3h] j 3.12 [s, 3hJ; 3.15 [m, 3h "]; 4, lo [m, 3HJ; 5.84 [bs, Hi] _5, £ 6.94 m, 2h] ; £ 7.76 d, 9.5 Hz, IH j; 9, ο | ~ bs, 2

Example Io

Reaction of the chlorohydrin derivative of 4- (sec-butylsulfonyl) phenol with isopropylamine according to the working groups of Example 1 (a) provides the 1- (isopropylamino) -3- [/ ± - (sec-butylsulfonyl) phenoxyj-2-propanol.

Example 11

Reaction of the chlorohydrin derivative of 4- (isopropylsulfonyl) -m-cresol with tert-butylamine according to the procedure of Example 1 (a) gives the 1- (tert-butylamino) -3- [4- (isopropylsulfonyl) -m-tolyloxyj -2-propanol.

Example 12

Reaction of the chlorohydrin derivative of 4- (methylsulfonyl) -3 Isopropylphenol with isopropylamine according to the procedure of Example 1 (a) gives the 1- (isopropylamino) -3-Mi- (methylsulfonyl) 3-isopropylphenoxy7-2-propanol.

509841/1047

Claims (1)

Claims or a pharmaceutically acceptable acid addition salt of which: R _{1 represents} a branched chain alkyl group of 3 or ¹ t inclusive carbon atoms, phenoxyisopropyl or cycloalkyl of 3 to 6 carbon atoms inclusive; R is hydrogen, lower alkyl of 1 to 4 carbon atoms inclusive, or lower alkylsulfonyl of 1 to k carbon atoms inclusive; R is hydrogen or lower alkyl of 1 to 4 carbon atoms including represents-, R. is hydrogen or lower alkylsulfonyl of 1 to k carbon atoms inclusive; and only one of the radicals R ^ or R ^, stands for lower 'alkylsulfonyl. 2. 1- (Isopropylamino) -3- \ k- (methylsulfonyl) -m-tolyloxyj-2-propanol or the hydrochloride salt thereof. 509841/1047 M / 16 o38 - 22 - 3. 1- (Isopropylamino) -5- [4- (methylsulfonyl) phenoxy J-2-propanol or the hydrochloride salt thereof. l- (tert-butylamino) -3- | 4- (methylsulfonyl) -m-tolyloxy] 2-propanol or the hydrochloride salt thereof. 5 · 1- (Iso'propylamino) -3-1 4- (methylsulfonyl) -o-tolyloxy] 2-propanol or a pharmaceutically acceptable acid addition salt of that. : 6. l-CCyclopentylamino) -3-1 4- (methylsulfonyl) -m-tolyloxyj 2-propanol or the hydrochloride salt thereof. 7. 1- (tert -Butylamino) -3-1 4- (methylsulfonyl) phenoxy -2-propanol or the hydrochloride salt thereof " 8.! - (Cyclopropylamino) -3-j4- (methylsulfonyl) -ra-toiyloxy | - 2-propanol or the hydrochloride salt thereof. 9 · l- (phenoxyisopropylamino) -3-1 4- (methylsulfonyl) -mtolyloxyι-2-propanol or the hydrochloride salt thereof. lo. 1- (Isopropylamino) -3- [2- (methylsulfonyl) phenoxy] -2-propanol or the hydrochloride salt thereof. 509841/1047 M / 16 o38 - 23 - 11. Process for the preparation of the compounds according to Claims 1 to Io, characterized in that man (a) a phenol of formula II (II) -v-orin R ₂ , R, _ and R, which have the meanings given in claim 1, with a compound of the formula III QH-CH-CH ₂ -X '(III) wherein X is halogen or a group of the formula wherein R is the radical given in claim 1 stands, converts; and R stands for a hydrogenolusable one (b) then, when X is halogen, the reaction product of step (a) with an amine of formula IV 5G9841 Π (K 7 2513B06 M / l6 038 - 2 ^ι ί - (IV) wherein R. has the meanings given in claim 1 owns, condensed, or, when X is said j group of the formula j represents hydrogenating the reaction product of step (a) to remove the hydrogenolizable blocking group; and (c) if an acid addition salt of the compound of formula I is desired, the free base form of Reacting compound of formula I, which was prepared in step (b), with a suitable acid. 12. Medicament consisting of at least one compound according to claims 1 to Io together with pharmaceutically acceptable carriers and / or customary auxiliaries. 509841/1047