JPS5822478B2 - Alkylsulfonylphenoxypropanolamines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel alkylsulfonylphenokidibrobanolamines that have cardioselective β-adrenergic blocking properties and are useful in the treatment of heart disease.

The invention further relates to a process for making said compounds.

It is currently believed that there are at least two subgroups of β-atl/nalinergic receptors; β1-receptors and vasodilation, which are thought to mediate cardiac stimulation, and bronchodilation. β2-receptors (C, G) mediate smooth muscle relaxation, which is responsible for the effects of

Drery et al., C11nical Pharmacolo
gy and Therapeutics, 10 (
6), 765-799 (1969: Andori, Jack, The Pharmaceutical Journal
al, 237-240 (August 29, 1970))
.

Various derivatives of phenoxypropanolamine have been reported in the prior art to have β-adrenergic blocking properties (see, for example, Dutch Patent No. 6907700 and Belgian Patent No. 762629).

However, while the above-mentioned Dutch patent generally discloses pharmaceutical products containing various substituted (including alkylsulfonyl) phenoxypropanolamines, it does not specifically disclose the class of alkylsulfonylphenoxypropanolamines of the present invention. I haven't.

The present invention is based on the formula (1) where R1 is (isopropyl, secondary butyl,
a branched chain alkyl residue of 3 or 4 carbon atoms (such as isobutyl and tertiary butyl), phenoxyisozorobyl or cycloalkyl of 3 to 6 carbon atoms; R2 is hydrogen, 1 to 6 carbon atoms; lower alkyl of 4 carbon atoms,
or lower alkylsulfonyl of 1 to 4 carbon atoms; R3 is hydrogen or lower argyl of 1 to 4 carbon atoms; R4 is hydrogen or lower alkylsulfonyl of 1 to 4 carbon atoms; and one and only one of R2 and R4 is lower alkylsulfonyl) or a pharmaceutically usable acid addition salt thereof.

Preferred compounds of the invention have the formula (wherein R&ζ lower alkyl, R1 and R
3 is as defined above, and only one of R3 is lower alkyl), as well as pharmaceutically usable acid addition salts thereof.

Another preferred m= group of the argylsulfonylphenoxypropanolamines of the present invention is represented by the formula (1) (wherein R1,
R3 and R are as previously defined.

Examples of compounds of formula IX are: ■-(isozolobylamino-3, , , , -(4-, -(methylsulfonyl)-1-11-1-IJroxy]-2- Zolopanol, 1-(tertiary butylamino)-3-C4-(methylsulfonyl)-m-) lyloxy]-2-propatol, ■-(isopropylamine)-3-[4-(methylsulfonyl)phenoxylo2 -gropanol, and 1-(tert-butylamino)-3-(4-(methylsulfonyl)phenoxy)-2--j lovanol.

A preferred group of compounds of formula IX are those where R1 is isopropyl or tertiary butyl and R4 is methylsulfonyl.

The term "lower argyl" as used herein includes both straight and branched chain carbon residues of 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, 1- 7"al, ■=methylgufurol, 2-methylzorobyl, and tertiary butyl.

Examples of cycloalkyl groups of 3 to 6 carbon atoms include cyclopropyl, /clobutyl, cyclopentyl and cycloalkyl.

As used herein, the term "pharmaceutically usable acid addition salts" includes, for example, acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, cinnamic acid. , sulfonic acids such as fumaric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfamino acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and related acids. Refers to a salt of a compound of formula (2) formed with an inorganic or organic acid.

Acid addition salts of the invention can be prepared, for example, by treating a solution or suspension of the free base in a reaction-inert organic solvent with the desired acid and then forming the salt by concentration under reduced pressure or by crystallization techniques. Manufactured using conventional methods such as recycling.

Insofar as the compound of formula (1) has at least one asymmetric carbon, the present invention also includes all possible optically active forms and racemic mixtures of the compound.

The resolution of the racemic mixture to obtain the optically active isomer of the compound of formula (1) is carried out by the conventional method used in the resolution of phene I-ruamino, for example, d-tartaric acid, cihenzoyl-monotartrate, rest-camphorsulfonic acid. , d is carried out by salt formation using an optically active acid such as mandelic acid, followed by fractional crystallization.

The present invention also relates to a compound of the formula
cycloalkyl of 1 to 4 carbon atoms; R2 is hydrogen, lower alkyl of 1 to 4 carbon atoms, or alkylsulfonyl of 1 to 4 carbon atoms; R3 is hydrogen or cycloalkyl of 1 to 4 carbon atoms; is lower alkyl of hydrogen atoms; R4 is hydrogen or lower alkylsulfonyl of 1 to 4 carbon atoms, one of R2 and R4 and one
In the method for producing an alkylsulfonylphenoxyzolopanolamine having the formula (wherein R2, R3 and R4 are lower alkylsulfonyl) or a pharmaceutically usable acid addition salt thereof, (as defined above) is a phenol of the formula ■ [wherein X is a halogen or a formula (wherein R1 is as defined above and R5
is a hydrolyzable residue (such as benzyl or benzhydryl); (b) then when X is halogen (preferably chlorine or bromine), step The reaction product of a) is expressed as formula % formula %
() in which R1 is as defined above, or when X is said group of the formula -N-R, the reaction product of step a) (C) If an acid addition salt of a compound of formula (1) is desired, the free base of a compound of formula (1) formed during step (mb) A method is provided which is characterized in that the form is reacted with a suitable acid.

The alkylsulfonylphenols of formula (1) are obtained by oxidizing the corresponding alkylthiophenols with hydrogen peroxide according to standard procedures.

RoB, Wagner and H,D, Zuk, Synthe
ticQrganic Chemistry, 801
See (Willey, 1953).

Since the epihalohydrin molecule of formula (1) has two reactive positions, the reaction with the phenol of formula (2) results in two (2) and (2) reaction products (wherein R2, R3, R4, and (as defined in ).

However, during the subsequent steps of this method, the formula V and the formula ■
The two possible intermediates yield the same final product of the invention upon condensation with an amine of formula (1).

As a result, 2 and
It is not necessary to carry out a separation of the mixture of intermediates.

If desired, the epi-lohydrin reaction product can be taken up in an inert solvent such as chloroform and shaken with excess concentrated hydrochloric acid to convert the epoxide of formula ■ to the corresponding sulfonylphenoxyhalohydrin of formula II. It's fine.

Conversely, if desired, conventional methods may be used, e.g.
The halohydrin of ⑐V may be converted to the corresponding epoxide of formula ① by reaction with a base by the procedure described in ).

The interaction of the phenol of formula (1) with the epihalohydrin of formula (2) is carried out using an excess of epihydrin 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.

The interaction of a phenol of formula II with an epihalohydrin of formula ■ has been described by YoM, Beasley et al., J. pharm.

Pharmacol 0.10.47-59(1
It can also be carried out in a basic medium, for example caustic soda, as well as at ectotherm, according to the procedure of 958).

The condensation of the epihalohydrin reaction product with the amine of formula (1) is preferably carried out in an organic solvent that is inert under the reaction conditions, such as ethanol, toluene, dioxane.

This reaction can also be carried out in the absence of a reaction solvent by using an excess of an amine such as isopropylamine or tertiary butylamine.

When a compound of formula (1) is reacted with a compound of (2) when X is a group of formula, i.e., a group of formula ) reaction products are formed.

A compound of formula (1) is converted to a compound of formula (2) by hydrogenation.

Removal of the hydrolyzable protecting group R5 can be carried out by catalytic hydrogenation, for example in the presence of a palladium on charcoal catalyst in an inert solvent, such as ethanol or aqueous ethanol.

Compounds of formula (1) can be obtained by known methods.

For example, shrimp with N-benzylisopropylamine in an alkaline medium (e.g., aqueous liquid) as described by L. Vuilla et al., Farma Co0, Scientific Edition, 24(3), 349-357 (1969). Obtained by reaction with chlorohydrin.

The cardioselective β1-adrenergic activity of the compounds of the invention can be evaluated in standard in vitro drug test systems such as spontaneous beating rabbit atrial preparations and guinea pig tracheal preparations.

The following Table 1 shows hydrochloric acid 1-(ingropyramine)-3-
C4-(methyl[sulfonyl)-3-)lyloxy) -
Figure 2 compares the potency ratio of 2-7' lovanol and the clinically useful beta-adrenergic receptor antagonist propranolol and illustrates the cardioselectivity of the compounds of the invention.

1-(Ingropyramine)-3-114-(methylsulfonyl)3-FI hydrochloride, which is a preferred compound of the present invention
Jroxy]-2-gropanol was 0.71 mq/each.
kg body weight and a standard challenge dose of 2.02 In9/kg (intravenously) suppresses the increased contractile force induced under anesthesia.

Another important property of the compounds of the invention is that they are less toxic in supplements.

For example, hydrochloric acid 1-(ingropyramine)-3-[4
-methylsulfonyl) -m-1□ IJroxy) -
For 2-j lovanol, the oral LD, o values in mice and rats were 1504 and 1792m9, respectively.
/kg body weight; the intravenous LD5° value in mice is 339 my/kg body weight.

The compounds of the present invention represented by formula (II) are useful in the prevention and treatment of heart diseases such as angina pectoris, arrhythmia, cardiovascular anxiety (neurasthenia) and hypertension.

Since the argylsulfonylphenoxyamines of formula (■) have selective β1-adrenergic blocking activity,
It is of particular value in the treatment of heart disease.

Compounds exhibiting this selective action may exhibit the inotropic and chronotropic effects of catecholamines, such as epinephrine and isoproterenol, on beta2-adrenergic receptors in the trachea and vascular muscles (without affecting them). preferentially blocks the chemical effects.

For the purpose of controlling cardioselective β1-adrenergic blocking activity, the alkylsulfonylphenoxypropanolamines of formula (1) may be administered to mammals either lightly or parenterally at a dose of 0.05 to 20 m/kg body weight. I can do it.

Preferably, the compounds of the present invention are used to reduce β of mammalian smooth muscle tissue.
- A sufficient amount is administered to the mammal to reduce the inotropic, chronotropic effects of the β-adrenergic agonist without appreciably affecting adrenergic receptors.

The alkylsulfonylphenoxypropanolamines of formula (■) are formulated by blending with a pharmaceutically acceptable carrier.
Pharmaceutical compositions can be provided in unit dosage form suitable for administration to mammals.

The pharmaceutical composition can be prepared in the form of tablets, capsules 1. It may take the form of powder, granules, suspension, solution, etc.

Suitable pharmaceutical carriers may be organic or inorganic and include corn starch, lactose, calcium phosphate,
Stearic acid, polyethylene glycol, water, sesame oil,
solids, such as peanut oil, propylene glycol, etc.
Contains liquid.

Pharmaceutical compositions are prepared using standard formulation procedures.

The following examples are presented solely for the purpose of illustrating the preparation of compounds of the invention and are not meant to be limiting in any way.

The nuclear magnetic spectrum data reported in the following examples are:
Chemical shifts (δ) in ppm, multiplicity for that shift including coupling constants (H, Z, = J values) where appropriate, and the relative area under the curve for each chemical shift corresponding to the number of protons. including.

The symbols for multiplicity are: sl singlet; b
s, wide singlet; d, doublet; m, multiplet.

Tetramethylsilane was used as an internal standard.

Example 1 (a) 18.6? A mixture of (0,1 mol) of 4-(methylsulfonyl)-m=cresol, 6 (1 (0,05 mol)) of epichlorohydrin and 0,6 of pyrrolidine is heated on a steam bath for 12 hours.

Excess epichlorohydrin is removed under reduced pressure.

The obtained chlorohydrin derivative was dissolved in absolute ethanol (5c)
ml and filter through diatoms.

This epichlorohydrin derivative contains 5C in ethanol lachrymal fluid.
1 (0.85 mol) of isopropylamine and 0.17 of potassium iodide are added.

The resulting mixture is refluxed for 18 hours and then; filtered.

The solution is filtered under reduced pressure to obtain a residue, which is taken up in 70 ml of IN hydrochloric acid and 3001 TL of absolute ethanol.

Distillables are removed under reduced pressure and the resulting residue is stirred with ether to obtain a solid crude product.

The crude product was crystallized from butanone-methanol and then recrystallized from 95% ethanol-ether to give hydrochloric acid 1-(isopropylamine)-3-(4-(methylsulfonyl)-triloxy)-2. −Property tools,
mp 1.77.0-179.0°C is obtained with a total yield of 62%.

- Analysis of sample, mp 176.0-178.0'C (corrected) was as follows: Analysis Calculated value as C14H23NO4・■■C1: C
,49,77:H,7,16:N,4.15゜1 Experimental value: C,49,72;H17,16;N4
．． 08° nuclear magnetic resonance, DMSO4-d6, δ (ppm): 1.2
8(d, 6.5Hz, 6I(): 2.58(s,
3H): 3.11 (s, 3H,l: 3.
13cm.

3H): 4.11 (m, 3H] near, 01 (m, 2H)
: 7.77Cd, 9.2Hz, IH); 8.9 (b
s, 2H].

(b) Using aqueous caustic soda as the reaction medium, ■-(isopropylamino)-3
-(4-(methylsulfonyl)-triloxy) -
To produce 2-gropanol, add 250% water at 230°C.
37.2L in ml? (0,2 mol) of 4-(methylsulfonyl L-m-cresol) and 13P (o, 32 mol) of caustic soda for 5 minutes.
(0.4 mol) of epichlorohydrin is added in small portions.

The final pH of this solution is 8-8.5.

The reaction mixture was extracted twice with 250 ml each of chloroporum.

The chloroform extract was dried over sodium carbonate and filtered for 1 hour.
, P solution is concentrated under reduced pressure to obtain a crude shrimp chlorohydrin derivative.

This epichlorohydrin derivative was mixed with ethanol 150r/
17P (0,286 mol) in 2 ml of water
of isozolobylamine.

After stirring for 10 minutes, the mixture is refluxed for 4 hours and the distillables are removed under reduced pressure.

The resulting residue was taken up in ethanol and acidified with ethanolic hydrogen chloride to give hydrochloric acid 1-(isopropylamine)-
3-(4-(methylsulfonyl)-m-)'Jroxy]
-2- Proper tools are obtained.

(e) Further modified 1-(isopropylamine)-
3-(4-(methylsulfonyl)-triloxy]-
The method for producing 2-propatol uses a hydrolyzable protecting group and is as follows:1. -((N-
benzyl)isozolobylamine]-2,3-epoxypropane in ethanol with 4-(methylsulfonyl)-m-
1-((N-benzyl)isopropylamine)-3-4-(methylsulfonyl)-m by reacting with cresol
- Obtain the IJ Roxy 2-proper tool.

The reaction mixture is filtered, acidified with ethanolic hydrogen chloride, the benzyl protecting group is removed by catalytic hydrogenation using a palladium on charcoal catalyst, the catalyst is collected, the liquid is concentrated and the hydrochloric acid 1-(isopropylamine)- 3-(4-(methylsulfonyl)-m-triloxy]-2-gropanol is obtained.

Example 2 According to the procedure of Example 1(a), 4-(methylsulfonyl)-
The reaction of a chlorohydrin derivative of m=cresol with tertiary butylamine and crystallization from acetonitrile yields hydrochloric acid 1-(tert-butylamino)-3-(4-(methylsulfonyl)-triloxy]-2- Gropanol,
mp 175.0-176.0°C (hardening and remelting at 197,0°C) (correction) is obtained.

analysis.

Calculated value as C15H25NO5□5-HCI: C,5
1,20; H17,45; N, 3.98° Experimental value: C, 50,99; H17,72; N14.2
0° nuclear magnetic resonance, DMSO-d6, δ (ppm): 1.31
(s, 9H'); 2.59 (s, 3H); 3.02
(m, 2H); 3.11 (s, 3H,): 4.10
(rn, 3H); 6.97 (m, 2H); 7.7
5 (dl 95Hz, II (); 8.7 (bs, 2H)
.

Example 3 Following the procedure in Example 1 (a) 4-(methylsulfonyl)
Reaction of the chlorohydrin derivative of phenol with isopropylamine, crystallizing it from ethanol, yields 1-(isozolobylamine)-3-(4-(methylsulfonyl)phenoxy)-2-propatur hydrochloride, mp 1
A temperature of 93.0 to 195.0°C is obtained.

analysis.

Calculated value as C13H2□No4S-HCI: C, 48
, 22; H, 6,85; N, 4.32° Experimental value: C, 48,00; H, 7,02; N, 4.25
゜Nuclear magnetic resonance, DMSOd6, δ (ppm): 1.28
[d, 6.5Hz, 6H); 3.12 (
m.

3H): 3.14 (s, 3H): 4.13
(m.

3H): 5.91 Cd, 4.2Hz, LH) Near, 13 (m, 2H); 7.80 (m, 2
IyL); 8.9 (bs, 2H).

Example 4 Following the procedure of Example 1(a), 4-(methylsulfonyl)-
Recrystallization from butanone by reaction of the chlorohydrin derivative of 9-cresol with isopropylamine yields
1-(isopropylamino)-3-(4
-(Methylsulfonyl)-0-triloxy]-2-propatol, mp 118.0-1.20.0°C is obtained.

analysis.

Calculated value as C14H21NO4・HCl: C, 50,
07; H, 6,60; N, 4.17° Experimental value 2C, 50,23; H, 6,76; N, 4.42
゜Nuclear magnetic resonance, CDCl3, δ (ppm): 1.10 (
d, 6.4Hz, 6HJ: 2.27(s, 3J()
;2.50 (bs, 2H) : 2.85 (m1
3HJ; 2.99 (s, 3H): 4.11 (m
, 3H]; 6.86 (d, 9.3Hz, LH
): 7.65 (m.

2H).

Example 5 Example 1 1-(tert-butylamino)-3-(4-(methylsulfonyl:phenoxy) sea 2
- Get property tools.

This free base was converted to the hydrochloride salt.

mp 221.0-223.0°c.

analysis.

Calculated value as C14N23 NO4・HCI: C,4
9,77; N17.16; N, 4.15° Experimental value: C, 50,10; H, 7,33; N, 4.00
Example 6 1-(Cyclopropylamino)-3-(4-(methylsulfonyl) is produced as the free base by reaction of the chlorohydrin derivative of 4-(methylsulfonyl-m-cresol) with cyclopropylamine following the procedure of Example 1(a). )-m
-t')roxy,]-2-7'' lovanol is obtained.

This free base was converted to the hydrochloride salt.

mp144. ．． 5-147.5°C. analysis.

Calculated value as Cl4H21NO4・HCI: C, 50,
07; Hl 6.60; N, 4.17° Experimental value: C, 50,23; H, 6,76; N, 4.02
゜Example 7 Following the procedure of Example 1(a), 4-(methylsulfonyl)-
Reaction of the chlorohydrin derivative of m-cresol with phenoxyisopropylamine gives 1-(
phenoxyisopropylamine)-3-(4-(methylsulfonyl)-m=triloxy]~2-propanol is obtained.

This free base was converted to the hydrochloride salt.

mp 143.5-147.5°C analysis.

Calculated value as C2oH27N05S: C, 61,05;
H, 6,92; N13.56° Experimental value: C161,12; H, 7,14; N, 3.32
Example 8 1-(isopropylamine)-3 to [2-(methylsulfonyl)phenoxy)- as the free base by reaction of the chlorohydrin derivative of 2-(methylsulfonyl)phenol with isopropylamine according to the procedure of Example 1(a).
Obtain 2-propanol.

This free base was converted to the hydrochloride salt.

mp 187.5~189.5°C0 analysis.

Calculated value as C13H21NO4S-HCl: C148
,22; H, 6,85; N, 4.32° Experimental value: C, 48,19; H, 7° 05; N14.37
゜Example 9 Following the procedure in Example 1 (a), 4-(methylsulfonyl)
-Reaction of m-cresol with the chlorohydrin derivative nocyclopentylamine to produce 1-(cyclopentylamino l-3-(4-(methylsulfonyl)-m-)ryloxy)-2-gropanol, mp 183.0-185
．． 0°C (corrected).

analysis.

C16N25 NO,S - Calculated value as HC1: C,
52,81; H, 7,20; N, 3.85° Experimental value: C, 53,04; H, 7,37; N13.6
9° nuclear magnetic resonance, DMSOda, δ (ppm); 1.70
(m, 9H); 2.58 C8,3H]; 3.1
2(s, 3H, 1; 3.15(m, 3H); 4.10(
m, 3H); 5.84 (bs, LH); 6
．． 94 (m, 2H]; 7.76 (:d, 9.5Hz.

LH); 9.0 (bs, 2H″J.

Example 10 The reaction of 4-(sec-butylsulfonyl)phenol with the chlorohydrin derivative neuglobilamine according to the procedure in Example 1 (a) yields 1-(isopropylamine)-3.
-(4-(sec-butylsulfonyl)phenoxycou2-
Get Gropanol.

Example 11 Following the procedure of Example 1 (a), 1-(tert-butylamino)-
1-C4-(isopropylsulfonyl)-m-)! J Roxy]-2-Get the property tool.

Example 12 4-(Methylsulfonyl) following the procedure in Example 1 (a)
-1-(isozolobylamine)-3-C4,-,-(methylsulfonyl)- by reaction of chlorohydrin derivative of 1-inzolobylphenol with isozolobylamine
3-isozolobylphenoxy)-2-propanol is obtained.

The gist of the present invention, embodiments of the target compound, and related matters are as follows.

(1) Method described in the claims.

(2. Target compound of the claims.

(3) 1-(isozolobylamine)-3-(4-(
(2) above, which is methylsulfonyl)-m-t') fuxy-2-propatool or its hydrochloride;
Compounds described.

(4) 1-(inpropylamine)-3-C4-(
The compound according to (2) above, which is methylsulfonyl)phenoxy)-2-propatol or its hydrochloride.

(5) The compound according to (2) above, which is 1-(tertiary-butylamino)-3-[4-(methylsulfonyl)-m-)IJroxy)-2-7'' lovanol or its hydrochloride .

(6)]-(isozolobylamine-3-(4-(methylsulfonyl)-o-*')fuxi-2-propatool or a pharmaceutically usable acid addition salt thereof; (2) above; Compounds described.

(2) The above (2) is 1-(cyclopentylamine)-3-[4-(methylsulfonyl)-men-'t')roxy]-2-propanol or its hydrochloride.
Compounds described.

(8)1. -(tertiary butylamino)-3-[4-(methylsulfonyl)phenoxy-2-glopanol or the compound according to (2) above, which is a hydrochloride thereof.

(9) The compound according to (2) above, which is 1-(cyclopentylamino)-3-(4-(methylsulfonyl)-triloxy]-2-propatol or its hydrochloride.

(10) I-(phenoxyisozolopylamine)-3-
(4-(methylsulfonyl)-m-triloxy]-2-
1h consisting of glopanol or its hydrochloride;
The compound described in (2).

The compound according to (2) above, which is Oυ 1-(isopropylamine)-3-[2-(methylsulfonyl)phenoxy)-2-7'' lovanol or its hydrochloride.

The alkylsulfonylphenoxypropanolamine of formula (1) described in any of the formulas (2) and (2) above exhibits a β-adrenergic effect without any observable effect on β-adrenergic receptors in smooth muscle tissue of mammals. A method for expressing a cardioselective β1-adrenergic blocking effect, which comprises orally or parenterally administering to the mammal an amount sufficient to reduce the inotropic and chronotropic effects of the agonist. .

(13) The compound of formula (1) was administered to the mammal at 90% per kg body weight.
The above-mentioned method consists of administering doses from 05 to 20η.

(2) A method for producing a pharmaceutical having a cardioselective β1-adrenergic blocking effect, which comprises preparing the compound of formula (2) described in (2) above into a dosage form suitable for medical purposes.

(15) A tangible pharmaceutical having a cardioselective β1-blocking effect produced by the method described in ia.4) above.

(16) The above (2) in a known manner for similar compounds.
A process for preparing a pharmaceutical compound suitable for use in the above-mentioned process (1), characterized in that it produces a compound of formula (1) as described in (1) above.

Claims (1)

[Scope of Claims] 1 Formula ■ (wherein R1 is a branched chain alkyl residue of 3 or 4 carbon atoms, phenoxyisoprobyl or 3 to 6
cycloalkyl of carbon atoms; R2 is hydrogen,
is lower alkyl of 1 to 4 carbon atoms or lower alkylsulfonyl of 1 to 4 carbon atoms; R3 is hydrogen or lower alkyl of 1 to 4 carbon atoms; + R
4 is hydrogen or lower alkylsulfonyl of 1 to 4 carbon atoms; one and only one of R2 and R4 is lower alkylsulfonyl) or its pharmaceutical use In the process of preparing possible acid addition salts, (a) a phenol of the formula ■ (wherein R2, R3 and R4 are as defined above) is converted to a phenol of the formula ■ [wherein X is a halogen or a compound of the formula -N- R1Ro (wherein R1 is as defined above, R5
is a hydrolyzable residue); (b) Then, when X is rosin,
The reaction product of a) is condensed with an amine of the formula H2N-R1(IV), where R1 is as defined above, or X is a group of the formula -N-R, In some cases, the reaction 1 5 product of step (a) is hydrogenated to remove the hydrolyzable protecting group: (C) If an acid addition salt of the compound of formula ■ is desired, A process characterized in that the free base form of the compound of formula (1) formed in the emo group is reacted with a suitable acid.