Description

Field of the Invention

The present invention relates to novel, pharmacologically active compounds and to processes for their preparation. The invention aso relates to pharmaceutical compositions containing the compounds and to methods of their pharmacological use.

The object of the invention is to provide substances useful in the treatment, acute as well as long term, of cardiac arrythmias of diverse etiology.

Background Art

GB 1 433 920 discloses compounds of the formula

OCH ₂ CHOHCH,NH-A-X-R ^:

wherein R ^~~ for instance stands for an alkyl or cycloalkyl radical or an aryl radical, R ² for instance stands for halogen, CN or N0 ₂ radical, A stands for an alkylene radical of from 2 to 6 carbon atoms and X stands for -S-, -SO- or -S0 ₂ - radical.

These compounds are said to possess β-adrenergic blocking activity.

GB 1 457 876 discloses among others the compounds

NH ₂ COCH ₂ OCH ₂ CHOHCH ₂ NHCH ₂ CH ₂ NHSO_ y

and

y—CH ₂ CHOHCH ₂ NHCH ₂ CH ₂ NHS0 ₂ -C ₂ CH ₂ CH ₃

CONH ₂

These compounds are said to possess β-adrenergic blocking activity.

US 4 544 654 discloses among others compounds of the formula

wherein R may be lower alkyl, R ₂ may be hydrogen, n may be 0, 1 or 2, R ₃ and R ₄ may be hydrogen, lower alkyl, R _s and R ₆ may taken together form a saturated heterocyclic ring of from 4 to 8 ring members containing -S- linkage, wherein p O _p

is 0, 1 or 2 for use in the treatment of cardiac arrhythmias.

EP 245 997 describes antiarrhythmic agents of the formula

is ethylene or methylethylene, R is alkyl, X is O, S or a link, R, may be CONH,.

Disclosure of the Invention

The present invention concerns new compounds useful for treatment, acute as well as long term, of cardiac arrhythmias of divserse etiology.

An object is to provide antiarrhythmics which have less prominent side effects than existing antiarrhythmic drugs. The compounds should for instance be free of negative inotropic effect and the compounds may even be positively inotropic. The compounds should further separate the antiarrhythmic effect from central nervous and gastrointestinal effects.

The compounds of the invention are characterized by the general formula

and when appropriate in the form of a racemic mixture or in the form of a stereoisomeric compound and the pharmaceutically acceptable saltes threreof, in which formula

R is N0 ₂ , NHS0 ₂ CH ₃ or halogen,

X is O, CH ₂ , CHOH, CO, CONH, NH, S, SO, or S0 ₂ ,

n is an integer 0, 1 or 2,

Y is [CH ₂ ] _m , CHOH, CHOCH ₃ , CHNHR, CO or CHF

m is is an integer 0 or 1 and R is hydrogen, methyl or ethyl,

Z is hydrogen or a saturated or unsaturated, straight or branched alkyl group containing 1-3 carbon atoms.

/ \

A is a group -N S=* (O).

10

15

30

(O).

N - [CH ₂ ] _s - S - R _c

35

V (O).

Θ

- N - [CH ₃ ]_. - S - R

wherein R cL is hydrogen, a straight or branched group alkyl-OH, a straight or branched alkyl group containing 1-5 carbon atoms and optionally substituted by one or more fluoro atoms,

R is a saturated or unsaturated, straight or branched alkyl group containing 1-4 carbon atoms and optionally substituted by one or more fluoro atoms,

a cycloalkyl or an alkylcycloalkyl group, containing 3- 5 ring carbon atoms.

an unsubstituted phenyl group or a phenyl group substituted by one or more substituents selected from the group consisting of fluoro, hydroxy, methoxy, ethoxy, CN, CONH ₂ and NHS0 ₂ CH ₃ ,

Ra' is the same as R ₃ and independently of R _^ , ,

R , , is the same as R and independently of R ,

p is an integer 0, 1 or 2,

r is an integer 0, 1, 2 or 3,

s is an integer 2, 3, 4 or 5,

with the proviso that when X is CONH then A is other than

Halogen atoms in formula I comprise fluorine, chlorine, bromine and iodine.

Alkyl groups in formula I which are straight and saturated are for instance methyl, ethyl, n-propyl, n-butyl.

Alkyl groups in formula I which are straight and unsaturat are for instance vinyl, allyl, propenyl, -C≡CH, -CH ₂ -CH^C and -C=CCH ₃ .

Alkyl groups in formula I which are branched and saturated are for instance i-propyl, s-butyl, i-butyl, t-butyl.

Alkyl groups in formula I which are branched and unsaturat ^• are for instance

Alkyl groups in formula I which are substituted by fluorin are for instance 1-3 H for F in the definition for alkyl groups which are straight and saturated or branched and saturated for instance CH ₂ CHFCH ₃ , CH ₂ CH ₂ CF ₃ , CH ₂ CF ₂ CH ₃ etc.

Alkyl groups in formula I which are substituted by hydroxy, OH OH for instance CH ₂ -OH, CH ₂ -CH ₂ -OH, CH-CH ₃ , CH-CH ₂ -CH ₃ ,

OH OH OH OH

I I I I

CH ₂ -CH-CH ₃ , CH ₂ -CH ₂ -CH ₂ , CH-CH ₂ -CH ₂ -CH ₃ , CH ₂ -CH-CH ₂ -CH ₃ ,

OH OH

CH ₂ —CH ^_ CH—CH ₃ , CH —CH ₂ ~CH ₂ —CH ₂

Cycloalkyl groups in formula I are for instance cyclopropy

eye lobuty 1 , eye lopenty 1.

Alkylcycloalkyl groups in formula I are for instance

Substituted phenyl group in formula I would be substituted by one substituent in the ortho, meta or para position or b two substituents - the same or different - in the 2,3- position, 2,4-position, 2,5-position, 2,6-position, 3,4- position or 3,5-position, or by three substituents - the same or different - in the 2, 3, 4-position, 2, 3, 5- position, 2, 3, 6-position and 3, 4, 5-position.

A preferred group of compounds of the invention are obtaine when

R is NHS0 ₂ CH ₃ , chloro, fluoro or nitro _ι is 0, CH ₂ , CHOH, CONH, S, SO, SO _:

n is 0 or 1

is CHOH, CHF or (CH ₂ ) _m wherein m = 0,1

is hydrogen, methyl, ethyl.

is

RC. where Rc _a l is CH ₃ , C ₂ H ₅ , C ₃ H _V ,

OH

CH ₂ - CH ₂ - OH, CH ₂ - CH - CH ₃ ,

s = 3 or 4, p = 0,l,2, R_ = C ₃ H _V , C ₄ H ₃ , CH ₂

A preferred compound can also be a quarternary nitrogen compound, obtained from the preferred compounds above by alkylation at the amino group.

Particularly preferred compounds are

1-[ethyl[3-(propylthio)propyl]amino]-3-(4-nitrophenoxy)-2 - -propanol

N-[4-[3-[ethyl[3-(propylthio)propyl] mino]-2- -hydroxypropoxy3-phenyl]-methanesulfonamide

N-[4-[3-[ethyl[3-(propylsulfinyl)propyl]amino]-2- -hydroxypropoxy]phenyl]-methanesulfonamide

1-[ethyl[3-(propylsulfinyl)propyl]amino]-3-(4-nitrophenox y) -2-propanol

α-[(4-fluorophenoxy)methyl]-4-(propylthio)-1- -piperidineethanol

α-[(4-fluorophenoxy) ethyl]-4-(propylsulfinyl)-1- -piperidineethanol

α-[(4-chlorophenoxy)methyl]-3-[(propylthio)methyl]-1- -pyrrolidineethanol

α-[(4-chlorophenoxy)methyl]-3-[(propylsulfinyl)methyl]-l - -pyrrolidineethanol

1-[(4-fluorophenyl)thio]-3-[methyl[3-(propylthio)propyl]- amino]-2-propanol

1-[(4-fluorophenyl)thio]-3-[methyl[3-(propylsulfinyl)- propyl]amino]-2-propanol

1-4[(4-fluorophenyl)sulfinyl]-3-[methyl[3- -(propylsulfinyl)propyl]amino]-2-propanol

1-4[ (4-fluorophenyl)sulfonyl]-3-[methyl[3- -(propylsulfonyl)propyl]amino]-2-propanol

In many instances the compounds of formula I occur in stereoisomeric forms, such forms being due to for instance optical isomerism, geometric isomerism and conformations of molecules.

The tertiary amines of the invention can be quarternized with a lower alkyl group and the quarternary compounds have the same effect as the tertiary compounds.

The new compounds of this invention may be used therapeutically as a stereochemical mixture or in the stereochemical pure forms.

Pharmaceutical preparations

In clinical practice the compounds of the present invention will normally be administered orally, rectally or by injection in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, e.g. the hydrobromide, hydrochloride, phosphate, sulphate, sulphonate, sulphamate, citrate, lactate, maleate, tartrate, acetate and the like in association with a pharmaceutically acceptable carrier. Accordingly, terms relating to the novel compounds of this invention whether generically or specifically are intended to include both the free amine base and the acid addition salts of the free base, unless the context in which such terms are used, e.g. in the specific examples would be inconsistent with the broad concept.

The carrier may be a solid, semisolid or liquid diluent or capsule. These pharmaceutical preparations constitute a further aspect of this invention. Usually the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by

weight for preparations intended for injection and between 2 and 50% by weight for preparations suitable for oral administration.

To produce pharmaceutical preparations containing a compoun of the invention in the form of dosage units for oral application, the selected compound may be mixed with a soli pulverulent carrier, e.g. lactose, saccharose, sorbitol, annitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, gelatine or other suitable tablet excipients, and a lubricant such as magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol waxes, and the like, and then compressed to form tablets. If coated tablets are required, the cores, prepared as described above, may be sugar coated or film coated by conventional film coating polymers.

Dyestuffs may be added to these coatings in order to readil distinguish between tablets containing different active substances or different amounts of the active compound.

For the preparation of soft gelatine capsules (pearl-shaped closed capsules) consisting of gelatine and for example, glycerol or similar closed capsules, the active substance may be admixed with a vegetable oil. Hard gelatine capsules may contain granulates of the active substance in combination with solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin) , cellulose derivatives or gelatine or other suitable pharmaceutically acceptable constituents.

Dosage units for rectal application can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.

Liquid preparations for oral application may be in the form

of syrups or suspensions, for example solutions containing from about 0.2 to about 20% by weight of the active substance herein described, the balance being sugar alcohol and water optionally mixed with ethanol, glycerol or propyleneglycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and as a thickening agent, such carboxymethylcellulose, hydroxypropylmethylcellulose or the like.

Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about 0.5 to about 10 by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.

Suitable doses for oral administration of the compounds of the invention are 1-300 mg 1 to 4 times a day, preferably 20-80 mg 1 to 4 times a day.

Methods of preparation

The compounds of the invention may be obtained by any of th following methods:

A. The compounds of the formula I wherein

X = O or S n = 1

Y = CHOH

Z = H p = 1 or 2

Rc_i, Rc_ and s have the meaning given above,

can be prepared by reaction of a compound of the formula

with compound of the formula

it [CH ₂ ] _r - S

wherein R , R , R , s, r and p have the meanings given above.

The reaction is typically carried out in a suitable solvent such as isopropanσl or N,N-dimethylformamide. The mixture should be heated to a temperature in the range 40-100°C until the reaction is completed. Thereafter the product can be isolated by conventional methods.

The compounds of the formula I wherein p is an integer 1 o 2 can be obtained by oxidation of a compound of th formula I wherein p is an integer 0.

When the substrate is an amine it could be neutralized with a suitable acid, e.g. p-toluene sulfonic acid in solvent where the salt is soluble e.g. ethanol. When the sulfoxide (p=l) shall be prepared the temperature should be kept between -20-0°C. When the sulfone (p=2) should be prepared a temperature in the range 20-80 ^* 0

could be used .

C. The compounds of formula I wherein A is

and the symbols R , X, n, Y and Z are defined as above, can be obtained by reaction of a compound of the formula

wherein R and R, are defined as above with a compound of the formula

L - [CH ₂ ] _g - S - R _c

wherein L is a leaving group such as Br, Cl, I, O-Tos or O-Mes, and s, p, and R are as defined above.

The reaction is typically carried out in a suitable organic solvent such as acetonitrile, isopropanol or

N,N-dimethylformamide. A suitable organic or inorganic base such as triethyla ine or potassium carbonate is added to the mixture. The mixture is then heated to a temperature in the range of 40-100C until the reaction is completed after which the products can be isolated and purified by conventional methods.

Intermediates

The compounds of the formula

wherein

is N0 _2/ NHS0 ₂ CH ₃ or halogen,

X is O, CH _2/ CHOH, CO, CONH, NH, S, SO or S0 ₂ ,

n is an integer 0.1 or 2

Y is [CH ₂ ] _m , CHOH, CHOCH ₃ , CHNHR, CO or CHF,

m is an integer 0 or 1 and

R is hydrogen, methyl or ethyl,

Z is hydrogen or a saturated or unsaturated, straight or branched alkyl group containing 1-3 carbon atoms.

R CL is hydrogen, a straight or branched group alkyl-OH, a straight or branched alkyl group containing 1-4 carbon atom and optionally substituted by one or more fluoro atoms,

are valuable intermediates for the preparation of the compounds of the formula I via the method C. These intermediates are new and constitute a part of the invention.

The compounds of formula II are prepared by reaction of a compound of the formula

with a compound of the formula

wherein Rq, X, n and Ra_ have the definitions given above,

Other valuable intermediates are

R. (O),

HN - [CH ₂ ]_ - S - R, III

wherein R 9., RC, s and p have the meanings given above.

Examples of such intermediates are

C ₂ H _S HN - [CH ₂ ] ₃ - S - C ₃ H _V and

C ₂ H ₅ (O) HN - [CH ₂ ] ₃ - S - C ₃ H _V

Working examples

Example 1

1-[ethyl[3-(propylthio)propyl]amino]-3-(4-nitrophenoxy)-2 - -propanol

NO-

A solution of [(4-nitrophenoxy)methyl]oxirane (12.0 g, 61.5 mmol) and N-ethyl-N[(3-propylthio)propyl]amine (9.9 g, 56 mmol) in acetonitrile (100 ml) was refluxed over night and evaporated. The residue was treated with 2M hydrochloric acid (100 ml) and diethylether in a separatory funnel. The upper layer was discarded and the two remaining was treated twice with methylenechloride. The organic layers were combined, treated with 2M sodiumhydroxide, dried over sodiu sulphate and evaporated. Yield: 19.4 g of the title compound.

NMR: ¹³ C in CD1-.; 11.59, 13.35, 22.81, 27.00, 29.77, 34.27, 47.59, 52.42, 56.19, 65.85, 71.00, 76.74, 77.00, 77.25, 114.47, 125.70, 141.51, 163.76.

Example 2

1-[ethyl(3-propylsulfinyl)propyl]amino]-3(4-nitrophenoxy- 2 -propanol

NO,

A solution of l-[ethyl[3-(propylthio)propyl]amino]-3-(4- -nitrophenoxy)-2-propanol (3.0 g, 8.4 mmol) and toluene-4- -sulphonic acid (1.7 g, 8.7 mmol) in ethanol (60 ml) was stirred for 30 min. and cooled to -10°C. To the cooled solution was added 3-chloroperbenzoic acid (1.75 «g, 8.4 mmol) in small portions. The solution was stirred at room temperature for 1 h. After evaporation the residue was treated with methylene chloride, washed three times with sodium carbonate in water, dried over sodium sulphate and evaporated. The oily residue was purified by column chromatography on silica. Yield: 1.9 g of the title compound.

NMR: 13 C in CDC1 ₃ ; 11.224, 11.345, 13.162, 16.117, 20.373,

20.490, 47.523, 47.575, 49.704, 49.965, 52.244, 52.480, 54.332, 54.448, 56.141, 66.132, 70.893, 70.976, 76.743, 76.999, 77.254, 114.438, 115.286, 115.596, 125.621, 125.859, 141.384, 163.726.

Example 3

α-[ (4-fluorophenoxy)methyl]-4-(propylthio)-1- -piperidineethanol

A solution of [ (4-fluorophenoxy)methyl]oxirane (3.9 g, 23 mmol) and 4-(propylthio)piperidine (3.3 g, 21 mmol) in 2- propanol was refluxed over night. The solvent was evaporated och the residue was dissolved in hydrochloric acid. Washing with diethylether, alkalizing with sodium hydroxide and extracting with methylene chloride yielded 6.4 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 13.36, 23.10, 32.04, 32.73, 32.88, 40.77, 52.43, 60.38, 65.49, 70.99, 115.44, 115.63, 115.82, 154.80, 156.20, 158.09.

Example 4

α-[ (4-fluorophenoxy)methyl]-4-(propylsulfinyl)-l- -piperidineethanol

A solution of α-[ (4-fluorophenoxy)methyl]-4-(propylthio)-l- -piperidineethanol (6.4 g, 19.5 mmol) and toluene-4-sulfoni acid (3.7 g, 19.5 mmol) in methylene chloride (100 ml) was stirred for 1/2 h and cooled to -10°C. To this solution was added solid 3-chloroperbenzoic acid (6.1 g, 19.5 mmol). The mixture was stirred at -10°C for 1/2 h and at room temperature for 1 h. The solution was then washed with sodium carbonate followed by water and finely dried over sodium sulphate and evaporated. Recrystallization from diisopropylether/acetonitrile (3:1) gave 1.9 g of the title compound.

NMR: ¹³ C in CDC1.-; 13.21, 15.08, 24.76, 24.93, 51.25, 51.40 53.70, 58.82, 60.17, 65.63, 65.93, 70.86, 115.56, 115.62, 115.65, 115.84, 154.80, 156.42, 158.32.

Example 5

α-[ (4-chlorophenoxy)methyl]-3-[ (propylthio)methyl]-1- -pyrrolidineethanol

A solution of α-[(4-chlorophenoxγ)methγl]-3-(hydroxymethγl)- -1-pγrrolidineethanol (5.7 g, 20 mmol) prepared from fif-[(4- chlorophenyl)methyl]oxirane and 3-hydroxymethyl- pyrrolidine, and triethyl amine (2.2 g, 22 mmol) in methylene chloride was cooled to 0°C. To the cooled solution was added methane sulfonylchloride (2.3 g, 20 mmol) . The reaction was stirred at room temperature for 1 h. The solution was washed with sodium bicarbonate and water and evaporated. To a solution of sodium hydride (1 g, 22 mmol) in DMF (10 ml) was added dropwise 1-propanethiol dissolved in DMF (20 ml). This solution was stirred 1 h at room temperature. The mesylate was dissolved in DMF (20 ml) and was slowly added to the thiolate solution. The reaction mixture was stirred over night. Water (20 ml) and toluene (200 ml) was added and the solution was evaporated to dryness. The residue was purified by column chromatography on silica gel. Yield 2.2 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 13.32, 22.85, 30.44, 30.47, 34.32, 34.35, 37.19, 37.31, 37.68, 53.40, 53.60, 53.85, 53.87, 56.44, 56.68, 58.19, 58.21, 59.73, 59.77, 67.10, 67.14, 67.24, 67.27, 70.57, 70.66, 115.74, 125.57, 125.65, 129.11, 157.23, 157.29.

Example 6

α-[ (4-chlorophenoxy)methyl3-3-[ (propylsulfinyl)methyl]-1- -pyrrolidineethanol

A solution of α-[ (4-chlorophenoxy)methyl]-3-[ (propylthio)- methyl]-1-pyrrolidineethanol (2.2 g, 6.4 mmol) and toluene- -4-sulfonic acid (1.22 g, 6.4 mmol) in ethanol (60 ml) was stirred and cooled to -15°C. To this solution was added a solution of 3-chloroperbenzoic acid (1.49 g, 6.4 mmol) in ethanol (10 ml). The mixture was stirred at -10°C for a 1 h and at room temperature for 2 h. Dilution with acetonitrile (100 ml) and addition of solid calcium hydroxide (1.18 g, 1 mmol) gave a slurry which was kept over night with room temperature. The slurry was filtered and evaporated. The residue was dissolved in 2 M hydrochloric acid washed with diethylether and extracted with methylene chloride. The extract was washed with 2M sodium hydroxide, dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel yielded 1.3 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 12.95, 15.63, 30.63, 30.99, 53.10, 53.17, 55.28, 57.05, 57.12, 57.83, 57.91, 59.44, 67.16, 70.45, 115.68, 125.62, 129.1, 157.17.

Example 7

1-[ (4-fluorophenyl)thio3-3-[methyl[3-( ropylthio)propyl3- amino3-2-propanol

A solution of [[(4-fluorophenyl)thio]methyl3oxirane (18.4 g 0.1 mol) and N-methyl-3-(propylthio)-l-propanamine (14.7 g 0.1 mol) in 2-butanol was refluxed over night. The solvent was evaporated and the residue dissolved in 2*M hydrochlori acid and washed with diethylether. The solution was treated with sodium hydroxide to pH 12 and extracted with methylene chloride. Purifying by column chromatography on silica gel yielded 17.9 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 13.29, 22.75, 27.76, 29.62, 34.19, 39.86 42.00, 56.64, 62.48, 66.21, 115.73, 115.90, 131.19, 132.11, 132.17, 160.62, 162.58.

Example 8

1-[ (4-fluorophenyl)thio]-3-[methyl[3-(propylsulfinyl)- propyl]amino3-2-propanol

To a solution of l-[ (4-fluorophenyl)thio3-3-[methyl[3- -(propylthio)propyl3amino]-2-propanol (3.3 g, 10 mmol) in dioxan (20 ml) was added a solution of sodium bromite (1.5 g, 10 mmol) in water (10 ml) over a period of 15 minutes. The solution was stirred for 45 minutes. After evaporation, water (10 ml) was added and the solution was extracted with methylene chloride. Drying over sodium sulphate and evaporation gave an oily residue which was purified by column chromatography on silica gel. Yield: 1.2 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 13.18, 16.10, 20.32, 20.50, 39.90, 41,90, 49.70, 49.96, 54.37, 54.46, 56.41, 56.57, 62.38, 62.41, 66.39, 115.72, 115.89, 131.15, 132.06, 132.08, 132.11, 160.57, 162.53.

Example 9

1-[ ( -fluorophenyl)sulfinyl3-3-[methyl[3-(propylsulfinyl) propyl3amino3-2-propanol

A solution of l-[(4-fluorophenyl)thio]-3-[methyl[3-

(propylthio)propyl3amino3-2-propanol (3.3 g, 10 mmol) and toluene-4-sulfonic acid (1.9 g, 10 mmol) in ethanol (70 ml) was stirred and cooled to -15°C. To this solution was added a solution of 3-chloroperbenzoic acid (4.65 g, 20 mmol) in ethanol (10 ml). The solution was stirred at room temperature for 2 h. The reaction mixture was diluted with acetonitrile (100 ml) and solid calcium hydroxide (3.7 g,

50 mmol) was added. The slurry was filtrated and evaporated The residue was dissolved in 2 M hydrochloric acid, washed with 2 M sodium hydroxide, dried over sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel. Yield: 2.2 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 13.16, 16.06, 20.39, 20.44, 20.55, 41.97 49.72, 49.98, 54.37, 54.44, 56.40, 56.51, 61.84, 62.00, 62.58, 62.67, 62.84, 62.90, 63.04, 63.25, 63.88, 64.02, 116.29, 116.47, 125.89, 125.96, 126.30, 126.37, 139.22, 139.57, 139.67, 163.02, 163.13, 165.02, 165.13.

Example 10

1[ (4-fluorophenyl)sulfonyl3-3-[methyl[3-(propylsulfonyl)- propy3amino3-2-propanol

A solution of l-[ (4-fluorophenyl)thio3-3-[methyl[3-

-(propylthio)propyl3amino3-2-propanol (3.3 g, 10 mmol) and toluene-4-sulfonic acid (1.9 g, 10 mmol) in methylene chloride was stirred for 10 minutes. Solid 3-chloropεrben- zoic acid (8.62 g, 50 mmol) was added and the solution was stirred for 3 h at room temperature. To the solution was added methylene chloride (200 ml) and the solution was washed with sodium bicarbonate and water. The organic layer was dried over sodium sulphate and evaporated. The oily residue was purified by column chromatography on silica gel Yield: 2.5 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 12.93, 15.57, 19.42, 41.75, 49.87, 54.55 55.78, 60.68, 62.14, 63.14, 116.24, 116.42, 130.81, 130.89, 135.80, 164,60, 166,64.

To a solution of N-(2-bromoethyl)phthalimide (10.2 g, 0.04 mol) and ethyl (3-propylsulfinyl)ρropylamine (7.1 g, 0.04 mol) in 100 ml of acetonitrile was added K ₂ C0 ₃ (11.0 g, 0.08 mol) and Nal (6.0 g, 0.04 mol), whereafter the mixture was refluxed for three days. The solution was filtered and evaporated, and the resulting material was purified by dissolving in 2-M HCl, extracting with CH ₂ C1 ₂ , alkalizing with 2-M NaOH.

This product, N'-[N-ethyl-N-[3-(propylsulfinyl)propyl3- aminoethyl]phthalimide, (3 g, 8 mmol) was without further purification refluxed for 1 h with hydrazinhydrate (0.4 g, 8 mmol) in 10 ml MeOH, whereafter 10 ml of water was added and the solution was evaporated to dryness. The resulting material was acidified with 12 ml of cone. HCl, heated for 1.5 h to 90°, and left in refrigerator overnight. It was alkalized (2-M Na OH) and extracted with CH ₂ C1 ₂ , the organi layer dried (Na ₂ S0 ₄ ) and evaporated to dryness. Yield 0.8 g (45%) of colourless oil.

NMR: ¹³ C in CDC1 ₃ ; 11.63, 13.53, 16.37, 23.00, 30.02, 34.32, 39.73, 47.34, 47.63, 52.51.

b) 4-nitro-N'-[N-ethyl-N-[3-(propylsulfinyl)propyl]amino¬ ethyl3benzamide

To a solution of 4-nitrobenzoyl chloride (0.7 g, 3.8 mmol) in 25 ml of CH ₂ C1 ₂ was added a solution of N-ethyl-N-[3- -(propylsulfinyl)propyl3 iaminoethane (0.8 g, 3,8 mmol) and triethylamine (0.4 g) in 25 ml of CH ₂ C1 ₂ at 20°. The resulting solution was stirred overnight. After evaporation the resulting material was purified by dissolving in

2-M HCl, extracting with CH ₂ C1 ₂ , alkalizing (2-M NAOH) and thereafter extracting of the product with CH ₂ C1 ₂ . After drying (NA ₂ S0 ₄ ) and evaporation the pure product was obtained. Yield 0.4 g (28.5%).

NMR: ¹³ C in CDC1 ₃ ; 10.96, 13.28, 16.40, 20.93, 37.89, 47.00, 50.59, 51.72, 52.22, 54.99, 123.34, 128.56, 140.50, 149.25, 165.55.

Example 12

N-[4-[3-[ethyl[3-(propylthio)propyl]amino3-2- -hydroxypropoxy]phenyl3methanesulfonamide

a) 1-( -aminophenoxy)-3-[ethyl[3-(propylthio)propyl3amino3- -2-propanol

16.5 g of l-[ethyl[3-(propylthio)propyl3amino]-3-(4-nitro- phenoxy)-2-propanol was dissolved in 165 ml of ethanol and 47 ml of 2 M HCl and hydrogenated with Ra-Ni. The mixture was filtered and evaporated. The residue, 23.3 g was purified on a 600 g Si0 ₂ column. Yield: 11.0 g of the title compound

NMR: ¹³ C in Dioxane; 8.81, 9.21, 13.61, 23.10, 23.60, 24.03 28.77, 31.17, 49.19, 50.92, 51.67, 53.72, 55.38, 64.93, 70.83, 116.88, 123.91, 125.23, 159.00 ppm.

b) N-[4-[3-[ethyl[3-(propylthio)propyl3amino3-2- -hydroxypropoxy3phenyl3methanesulfonamide

4.4 g of l-(4-aminophenoxy)-3-[ethyl[3-(propylthio)propyl3- amino3-2-propanol and 1.9 g triethylamine was dissolved in 50 ml of dichloromethane and cooled to -5°C. To the cooled solution was added dropwise 1.6 g methanesulfonyl chloride. The solution was allowed to stand for 1 h and was then washed with tree portion of water. The organic layer was dried over sodium sulphate and evaporated. The oily residue was purified by column chromatography on silica gel. Yield: 2.8 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 11.43, 13.26, 22.69, 26.54, 29.85, 34.10, 39.43, 47.48, 52.32, 56.20, 68.04, 70.46, 115.17, 124.19, 129.56, 156.60 ppm.

Example 13

N-[4-[3-[ethyl[3-(propylsulfinyl)propyl3amino3-2-hydroxy- -propoxy3-phenyl3-methanesulfonamide

2.5 g of N-[4-[3-[ethyl[3-(propylthio)propyl3amino3-2- -hydroxypropoxy]-phenyl3methanesulfonamide was oxidized with 1.4 g of m-chloroperbenzoic acid in analogy with example 2. The yield was 1.1 g of the title compound.

NMR: 13 in CDC1 ₃ ; 11.26, 11.35, 13.17, 18.18, 20.34, 20.47,

38.39, 47.48, 47.51, 49.55, 49.80, 52.15, 52.43, 54.07, 54.18, 56.16, 66.31, 70.43, 70.48, 115.11, 123.95, 130.12, 156.56 ppm.

Example of pharmaceutical compositions

The following examples illustrate the preparation of pharmaceutical compositions of the invention. The wording "active substance" denotes a compound according to the present invention or a salt thereof.

Formulation A. Soft gelatin capsules

500 g of active substance were mixed with 500 g of corn oil whereupon the mixture was filled in soft gelatin capsules, each capsule containing 100 mg of the mixture (i.e. 50 mg o active substance) .

Formulation B. Soft gelatin capsules

500 g of active substance were mixed with 750 g of pea nut oil, whereupon the mixture was filled in soft gelatin capsules, each capsule containing 125 mg of the mixture (i.e. 50 mg of active substance).

Formulation C. Tablets

500 g of active substance were mixed with 200 g of silicic acid of the trademark Aerosil. 450 g of potato starch and 500 g of lactose were mixed therewith and the mixture was moistened with a starch paste prepared from 50 g of potato starch and distilled water, whereupon the mixture was granulated through a sieve. The granulate was dried and sieved, whereupon 20 g of magnesium stearate was mixed into it. Finally the mixture was pressed into tablets each weighing 172 mg.

Formulation D. Effervescing tablets

100 g of active substance, 140 g of finely divided citric acid, 100 g of-finely divided sodium hydrogen carbonate, 3.5 g of magnesium stearate and flavouring agents (q.s.) were mixed and the mixture was pressed into tablets each

containing 100 mg of active substance.

Formulation E. Sustained release tablet

200 g of active substance were melted togther with 50 g of stearic acid and 50 g of carnauba wax. The mixture thus obtained was cooled and ground to a particle size of at mos 1 mm in diameter. The mixture thus obtained was mixed with 5 g of magnesium stearate and pressed into tablets each weighing 305 mg. Each tablet thus contains 200 mg of active substance.

Formulation F. Injection solution

Active substance 3.0 mg

Sodium pyrosulfite 0.5 mg

Disodium edetate 0.1 mg

Sodium chloride 8.5 mg

Sterile water for injection ad 1.00 ml

Formulation G. Hard gelatine capsules

10 g of active substance was mixed with 400 g of lactose and finally 2 g of magnesium stearate was added. The mixture was then filled in hard gelatine capsules, each capsule containing 206 mg of the mixture (i.e. 5 mg of active substance) .

Formulation H. Tablets

50 g of active substance was mixed with 1500 g of lactose, 200 g of microcrystalline cellulose and 10 g magnesium stearate. Tablets of 5 mg active substance with a core weight of 176 mg were finally compressed.