Description

Field of the Invention

The present invention relates to novel, pharmacologically active compounds and to processes for their preparation. The invention also 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 arrhythmias of divers etiology.

Background Art

GB 1 433 920 discloses compounds of the formula

OCH _o CHOHCH _o NH-A-X-R ¹

wherein R for instance stands for an alkyl or cycloalkyl radical or an aryl radical, R 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 acitivity.

GB 1 457 876 discloses among others the compounds

NH ₂ C0CH ₂ - ^/ _ y OCH ₂ CHOHCH ₂ NHCH ₂ CH ₂ NHS0 ₂ - ^r

and

CONH,

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

Disclosure of the Invention

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

An object is to provide antiarrhythmics which have less prominent side effects than existing ant arrhythmic 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

0-(CH ₂ ) _n - Y - CH-A

and when appropriate in the form of a racemic mixture or in the form of a stereoisomeric component and the pharmaceutically acceptable salts thereof, in which formula

n is an integer 0,1 or 2

Y is [CH _? ] , CHOH, CH0CH ₃ , CHNHR or CHF,

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

R (0) • ^{( 0 )} _p

- N ³ - [CH ₂ 1 _$ - S - R _C r - ^Φ N - [CK^ _$ - S - R ₍ I

^R a ' '

wherein Rα, is a straight or branched hydroxyalkyl or 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,

Ra' is the same as Ra and independently of Ra ¹ '

Ra ¹ ' is the same as Ra and independently of Ra

p is an integer 0, 1 or 2,

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

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 unsaturated are for instance vinyl, ally!, propenyl, -C=CH, -CH ₂ -C≡CH 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 unsaturated are for instance

Alkyl groups in formula I which are substituted by fluorine are for instance 1-3 H changed 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 are for

OH OH OH OH

I ■ I I instance CH ₂ ~0H, CH ₂ ~CH ₂ -0H, CH-CH ₃ , CH-CH ₂ -CH ₃ , CH ₂ -CH-CH ₃ , CH ₂ -Ch' ₂ -CH ₂

OH

C ^: .π— H -0H.

Preferred groups of compounds of the invention are obtained when

n is 1

Y is CHOH. CHF or (CH, __. ⁾ ill wherein = 1

Z is hydrogen

A is N -(CH ₂ C) S -S- R , where

R I S CH< _j , CnH r , C H7 , CHrtCHnOH ,

CH ₂ CH0HCH ₃ ,

R is C«H _ς , C H , CHΛCHFCH. ₅ ,

s is 3, 4, p is 0, 1, 2.

Especially preferred compounds are the sulfoxides i.e. when p is 1

The following compounds of this group are especially preferred, compounds wherein

Y is CH0H or (CH ₂ ) _m ,

R _a is C ₂ H ₅ , CH ₂ CH ₂ 0H,

s is 3 , p is 1 ,

is C ₃ H ₇ _

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

Preferred compounds are

4-[3-[ethy1[3-(propylthio)propyl]aminoJ-2-hydroxy-propoxy 2benzonitrile,

4-[3- ethyl[3-(propylsulfinyl) propyl]amino]-2-hydroxypropoxy] -benzonitrile,

4-[3-[ethyl[3-(propylsuIfonyl)prop l]amino]-2-hydroxypropoxy]- benzonitrile

4-T3-[ethyl (3-(rnethylsulfinyl) propy aminoj-2-hydroxypropoxy - benzonitrile

3-^(4-cyanophenoxy)-N,N-diethyl-2-hydroxy-N-^3-(propyl-su lfiπyDpropyl _j - -1-propanaminiutπ iodide

4- 3-j_ethyl[_3-(propy1thio)propyl,amino,-2(R)-hydroxy-propox _- -benzonitrile

4- 3-_ethyl J3-(propylsulfinyl)propyl aminoj-2(R)-hydroxy-propoxyJ- benzonitrile

4-^3-_ethyl 3-(propylthio)propyl _^ amino _^ -2(S)-hydroxypropoxy,benzonitrile

4- 3-j5thyl_3-(propylsulfinyl )propyl _, amino _^ -2(S)-hydroxypropoxy - benzonitrile

4-. _. 3-.ethyl_4-(ethylthio)butyl amino, -2-hydroxypropoxy, benzonitrile

4- _. 3- ethy _4-(ethylsuIfinyl)butyl, amino,-2-hydroxypropoxy. benzonitrile

4-_3-_2-hydroxyethy1) 3-(propylthio)propyl,amino, propoxy, benzoni rile

4-,3- .(2-hydroxyethyl }_3-(propylsulfinyl) ropyl _^ amino _, propoxy - -benzonitrile

4- 3-L(2-hydroxyethyl} 3-(propylsulfonyl)propylJarπin | propoxyj- benzonitrile

4- [3- j 2-hydroxyethyl)[_3- (methyl thio) propyl _, / aminoj -propoxy - benzonitrile

4-'l_3-L(2-hydroxyethyl)(3-(methylsulfinyl)propyUaminoj propoxy,! - •benzonitrile

4-_3-_ethyl [3- (propyl sulf inyl) propyl, ¹ aminoj -2-hydroxypropoxy _^ ' - benzonitrile, addition salt with hydrochloric acid

4-j_3-;ethyl._3-(propylsulfinyl)propyV amino -2-hydroxypropoxy, - benzonitrile, addition salt with biphenyl-2,2'-diyl hydrogen phosphate

r ^Γ \ 1 η

4-L3- jnethyl _3-(2-propenyl-l-thiq/propyl _, amino, -2-hydroxypropoxy/

-benzonitrile

r " ^" .- "

4- 3-_ethyl _3- (2-f luropropyl )thio propyl, ^' amino. -2-hydroxypropoxyj

-benzonitrile

__. — r __. —. _

4-__3- ethyl _3-_(2-fluoropropyl)sulfinyl, propyl _, amino_ _^ -2-hydroxypropoxy -benzonitrile

4- 3-_ethyl _3-(propylsulfinyl )propyl,amino, -2-fluoropropoxy _^ -benzonitrile

More preferred compounds are

4-|_3-|_ethyl|_3-(propylthio)propyljaminoj-2-hydroxy-prop oxyjbenzonitrile,

5. 4- 3--ethyl|_3-(propylsulfinyl) propyl _j aminoj -2-hydroxypropoxyj-

-benzonitrile,

4- [3- ethylj3-(propylsulfonyl)propyl _, aminoj-2-hydroxypropoxy

-benzonitrile

10 r ~

3- (4-cyanophenoxy)-N,N-diethyl-2-hydroxy-N- _3- (propyl -sulf inyl ) propylj -

-1-propanamin um iodide

4- [3- [ethyl [ 3- (propyl thio) propylj ami no. ¹ -2(R)-hydroxy-propoxyj TEE -benzonitrile r Γ ' *

4- 3- ethyl 'J3-(propylsulfinyl )propyV amino, -2(R)-hydroxy-propox ,

-benzonitrile

20 4- _^ 3- _^ ethyl J3-(propylthio)propyl,amino, -2(S)- hydroxypropoxy, benzonitrile

4- _. 3- _. ethyl 3-(propylsulfinyl) ropyl,amino.-2(S)-hydroxypropox _. -benzonitrile

4-_3-_ethyl _4-(ethylthio)butyl ^; amino--2-hydroxypropoxy,benzonitrile

4- 3-_ethyl_4-(ethylsulfinyl)butyl, amino,-2-hyroxypropoxy _. benzonitrile

30 4- 3- (2-hydroxyethyl) J3-(propylthio)propyl _. ,amino _. propoxy benzonitrile

4- 3-_(2-hydroxyethyl)_3-(propylsulfinyl)propyl,am o _. propoxy, -benzonitr le

35 4- 3-_( -hydroxyethyl)_3-(propylsulfonyl)propyl _, amino, propoxy -benzonitrile

4- [3- [ethyl [3- ( 2-f luoropropyDthioJ propylj aminoj -2-hydroxypropoxyj -benzonitri le r r Γ Γ "Ϊ "■ ~ ^~

4- _L 3-lethyl 3- (2-fluoropropyl )sulf inylj propyl _, amino; -2-hydroxypropoxy./ -benzonitri le

- r Γ -| i

4- 3- [ethyl 3-(propylsulfinyl )propylJ mino -2-fluoropropoxyj-

-benzonitrile

The most preferred compounds are

4- ^r 3-r/.ethyl : ^r _3-(propylsulfinyl) propyl,1amino ^" ,•-2-hydroxypropoxy..

-benzonitrile,

4- .3-.ethyl _3-(propylsulfinyl)propyl,amino _, -2(R)-hydroxy-propoxy_; -benzonitrile

4-_3-.eth l _3-(propy1suIfiny1)propy1.amino. ^' -2(S)-hydroxypropoxy, -benzonitrile

4- .3- _. ethyl _4-(ethylsulfinyl)butyl.amino, -2-hydroxypropoxy.benzonitrile

4- 3- _(2-hydroxyethyl ) _3-(propylsulfinyl )propyl _j amino _, propoxy, -benzonitrile ^r . ~ ~~ -~ ~< —_ ~~ _\

4- ^' 3-_ethyl[_3-_(2-fluropropyl)sulfinylj Ipropylj amino; -2-hydroxypropoxyj

-benzonitrile

- - <~ —, 4- 3- _ethyl 3- (propyl sulf inyl ) propy Daminoj -2-f luoropropoxy, - benzonitri le

Particular ly preferred compounds are

4- 3- ethyl _3-(propylsulf inyl ) propyl _, amino_ -2-hydroxypropoxy _, -benzonitri le

4-[3-[ethyl [3-(propylsulfin-yl)propylJaminoJ-2(R)-hydroxy-propoxyj -benzonitrile

4-[3-[ethyl j3-(propylsulfinyl)propylJaminoJ-2(S)-hydroxypropoxyJ -benzonitrile

4- ι_3-|_(2-hydroxyethyl)|_3-(propylsulfinyl)propyljaminojprop oxyj -benzonitrile

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 quarternarized 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 stereoche ical 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 hydrobro ide, hydrochloride, phosphate, sulphate, sulphonate, sulpha ate, 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, seππ ^' solid 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 compound of the invention in the form of dosage units for oral application, the selected compound may be mixed with a solid pulverulent carrier, e.g. lactose, saccharose, sorbitol, mannitol, 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 readily 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 nay 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 o suspensions, for example solutions containing from about 0.2 to about 20* by weight of the active substance herein described, the balance being sugar alcohols 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 as carboxymethylcellulose, hydroxypropylmethylcellulose or the like.

Solutions for parenteral applications by injection can be prepared in a 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 agent and/or buffering agents and may conveniently be provided in various dosage unit ampoules.

Suitable doses for oral administration of the compounds of the inventio are 1-300 g 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 the following methods.

A. The compounds of the formula I wherein A is

(0).

l ^CH ₂ J: - S - R

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

wherein Ra, is as defined above with a compound of the formula

L - 1CH S - R.

2,'S

wherein L is a leaving group such as Br, Cl, I, mesyloxy or tosyloxy and s, p and R are as defined above. ^r c

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 (acid acceptor) such as triethyla ine or potassium carbonate is added to the mixture. The mixture is then heated to a temperature in the range of 40-100-C until the reaction is completed after which the products can be isolated and purified by conventional methods.

B. The compounds of the formula I wherein p is an integer 1 or 2 can be obtained by oxidation of a compound of the 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 a 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) shall be prepared a temperature in the range 20-80°C could be used.

C. The compounds of the formula I wherein

n = 1,

Y = CHOH,

Z = H, p = 1 or 2,

R,, R_ and s have the meaning given above,

can be prepared by reaction of a compound of the formula

CN

with a compound of the formula

?a (0),

HN - (CH ₂ ] ₅ - S - R _C

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

The reaction is typically carried out in a suitable solvent such as isopropanol or N,N-dimethylfor»amide. 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.

D. The compounds of the formula I wherein

n 1 Y CHOH Z H P 0. 1, 2

R , R and s having the meanings above, can be prepared by a reaction of a compound of formula

with a compound of the formula

(0).

- (CH ₂ ) _S

The reaction conditions are the same as described in method C above.

The product fror.i this reaction step, having the formula

^•■ I P

CH ₂ -NH - ^(CH 2>s ^■ S -

CN

is then alkylated by conventional methods by a suitable alkylating agent ooff aa ffoorrmmuullaa RRaa--LL,, wwhheerree LL iiss aa lleeaavviinngg ggrrooiup defined as above, to yield the compound of formula I as defined above.

When the sulfur atom in the product has a lower oxidation state (e.g. p = 0 or 1) it can be further oxidized to products with sulfur atoms of higher oxidation states (e.g. p = 1 or 2) described in method B above.

E. A compound of the formula

v/here R , R , n, p and s have the meaning above

can be prepared by reacting a compound of the formula

0-(CH ₂ ) _n -CH-CH ₂ -0-S0 ₉ M I OH

where M is a methyl or a 4-methyl-phenyl residue, with a compound of the formula

H-M - cm - S - R

The reaction is typically carried out in a suitable organic solvent such as acetonitrile or N,N-dimethylformamide. A suitable organic or inorganic base such as triethylamine or potassiumcarbonate is added to the mixture. The mixture is then heated to a temperature in the range of 90-100°C until the reaction is completed after which the products can be isolated and purified by conventional methods.

Intermediates

The compounds of the formula

wherein

n is an integer 0,1 or 2

Y is fcH ₂ j _m , CHOH, CH0CH ₃ , CHNHR or CHF,

is an integer 0 or 1 and

R is hydrogen, methyl or ethyl,

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

R _a is, a straight or branched hydroxyalkyl or alkyl group containing 1-4 ca atoms 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 A. These intermediates are new and constitute a 5c part of the invention.

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

T£ with a compound of the formula R - NH ₂

wherein n and R have the definitions given above.

Other valuable intermediates are

ZO

^R a <°>p

'I

wherein R , R , s and p have the definitions given above.

Such intermediates can generally be obtained by a reaction of a compound of the formula

>! P L - (CH ₂ ) _S - S - R _ς

30 where L is Cl,Br, I, mesyloxy or tosyloxy with an amine of tne formula

H ₂ N - R _a

35 A typical procedure in analogy with procedure A can be used.

Examples of such intermediates are

Other valuable intermediates for the preparation of the compounds of the formula I via method D are

CN wherein Y, Z, R , n, s and p have the definitions given above:

Especially valuable are those intermediates wherein s is 3 and p is 0 or 1 such as

0 - CH,2 - CH - CH. c NH - (CH ₂ ) ₃ S - C ₃ H ₇

< . OH

CN and

!'

0 - CH ₂ - CH - CH ₂ - NH - (CH ₂ ) ₃ - S - C ₃ H _y OH

CN

Working Examples

Example 1

4- [3- [ethyl [3-(propylthio)propyl] amino]-2-hydroxy-propoxy] -benzonitri le

a) 4-[3-(ethyla ino)-2-hydroxypropoxy]-benzonitrile

T5 86.0 g of 4-(oxiranylmethoxy) benzonitrile was dissolved in 250 ml acetonitrile and mixed with 29.7 g ethylamine in an autoclave. The mixture was heated in a boiling water-bath over night, evaporated and the residue was dissolved- in 2-M hydrochloric acid. This acidic waterlayer was washed twice with ether, alkalized with 10-M sodium

20 hydroxide and extracted with three portions of dichloromethane.

The combined organic layers were dried over sodiumsulfate and evaporated. The solid residue was recrystallized twice from a mixture of diisopropylether: acetonitrile (9:1). Yield 57 g of 4- 3-(ethylamino)-

25 2-hydroxypropoxy -benzonitrile.

NMR : ¹³ C in CDC1 ₃ ; 14.88, 43.93 , 51 .28, 67.60 , 70.77 , 104.31 , 115.26 _; 119.00, 133.93, 161 .93 pp

30 b) 4- ', 3- [ethyl 3-(propylthio) propyl] amino] -2-hydroxypropoxy] - -benzonitri le

4.7 g of 4-f 3- (ethylamino)-2-hydroxypropoxy _, -benzonitri le , 4.5 g of

l-bromo-3-(propylthio)-propane and 5.8 g potassium carbonate were mixed in 50 ml isopropanol and refluxed over night. The mixture was filtrated and evaporated. The residual oil 8.3 g was separated by column chro atography. Yield 4.9 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 11.44, 13.47, 22.62, 26.84, 29.56, 34.63, 47.44, 52.27, 56.03, 65.81, 70.47, 103.74, 115.08, 118.78, 133.57, 161.87, ppm

Example 2

4-[3- [ethyl 3-(propylsulfinyl ) propyl] amino ^' ] -2-hydroxypropoxy] benzonitri le

2.45 g of 4-J.3-.ethyl; _, 3-(propy1thio)propyV aminoj -2-hydroxypropoxyJ- benzonitrile and 1.4 f p-toluenesulfonic acid were mixed in 50 ml of ethanol. The mixture was cooled to -10 ^C C and 1.7 g of m-chloroperbenzoic acid was added in small portions. The mixture was stirred for 0.5 hour at -10°C and one hour at room temperature and then evaporated. The residue was dissolved in dichloromethane and washed with three portions of sodium carbonate and twice with water and thereafter dried over sodium sulfate, filtrated and evaporated. The residue, 2.3 g yellow oil was purified by column chromatography. Yield:1.4 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 11.21, 11.33, 13.11, 16.02, 20.30, 20.43, 47.41, 47.45, 49.69, 49.95, 52.18, 52.41, 54.29, 54.41, 56.06, 56.09, 66.08, 70.41, 70.49, 103.76, 115.09, 118.83, 133.62, 161.88 ppm

Example 3

4- [3- [ethyl [3- (propyl sulf onyl ) propyl] am ino] -2-hydroxypropoxy] ^■ -benzonitri le

7.3 g of 4- _^ 3- _^ ethyl ^' 3-(propylthio)propyljaminoj-2-hydroxypropoxyJ- benzonitrile was mixed with 4.2 g of p-toluenesulfonic acid in 75 ml of ethanol. To this mixture was added 10.1 g of m-chloroperbenzoic acid in small portions. The temperature was allowed to rise to 45°C during the addition. The mixture was then stirred at room temperature for three hours. After that the reaction was completed, the solvent was evaporated and the residue was dissolved in dichlcromethane, washed three times with sodiumcarbonate and twice with water. The organic layer was evaporated and the residue was dissolved in 2-M hydrochloric acid and washed three times with ether. The aqueous layer was made alkaline with 1-M sodium hydroxide solution and extracted with dichloromethane. The organic solutions were dried over sodium sulfate filtrated and evaporated. The crude product 5.4 g was purified by column chromatography. Yield: 3.2 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 11.41, 12.88, 15.64, 19.57, 47.44, 50.15, 51.88, 54.68, 56.04, 66.19, 70.45, 104.0, 115.2, 118.94, 133.79, 161.91 ppm

Example 4

4- [3- [ ethyl [3-(methylsulf inyl) propyl] amino] -2-hydroxypropoxy] -benzonitri le

The title compound was prepared in analogy with the methods described in examples 1 and 2.

NMR: ¹³ C in CDC1 ₃ ; 11.16, 11.27, 20.18, 20.31, 38.39, 38.50, 47.40, 51.87, 52.11, 52.17, 52.35, 56.02, 66.09, 70.37, 70.44, 103.68, 115.05, 118.79, 133.58, 161.83 ppm

Example 5

3-(4-cyanophenoxy)-N,N-diethyl-2-hydroxy-N-f3-(propylsulf inyl)propyl] -1-propanamin um iodide

5.0 g of 4-_3- ethyl[3-(propylsulfinyl)propyljaminoj -2-hydroxypropoxy _. ' -benzonitrile and 2.4 g ethyliodide were dissolved in 50 ml of acetronitrile and heated to reflux for 5 hours. Another portion of ethyliodide, 2.4 g, was added and the reflux continued over night. The solution was evaporated and the residual oil, 6.6 g, was separated by column chromatography. Yield: 4.0 g of the title compound.

NMR: ¹³ C in D ₂ 0; 8.07, 13.42, 16.75, 47.73, 53.78, 55.53, 57.57, 60.38, 64.41, 67.42, 70.78, 104.00, 116.45, 120.77, 135.39, 162.35 ppm.

Example 6

3- ethylj,3-(propylthio)propyljamiπo,-2(R)-hydroxypropoxyjbenz onitril

c

a) (4S)-2 ,2-Dimethy1-4-(4-cyanopheπoxy)methy1-1 ,3-dioxolaπe

A solution of 4 _^ -hydroxy benzonitrile (55 g) in methanol (100 ml) was treated with potassium hydroxide (29 g) in water (30 ml) and evaporated at reduced pressure. The remaining potassium salt was dissolved in dry dimethylformamide (75 ml) and (4R)-2,2-dimethyl-4 - taethanesulfonyl- oxymethyl-l,3-dioxolane, 82.2 g, was added. The mixture was heated with stirring at 110°C for 20 h, allowed to cool and distributed between ether and water. The aqueous phase was extracted three times with ether, the combined ether phases washed three times with 10 aqueous potassium hydroxide and twice with water, dried over anhydrous sodium sulfate and evaporated. Yield 77 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 25.11, 26.57, 66.35, 68.85, 73.55, 104.30, 109.77, 115.17, 118.83, 133.79, 161.68 ppm.

b) (2R)-3-(4-cyanophenoxy)propane-1,2-diol

77 g of (4S)-2,2-dimethyl-4-(4-cyanophenoxy)methyl-l ,3-dioxolane, was dissolved in methanol (200 ml) and water (75 ml). Concentrated hydrochloric acid (0.5 ml) was added and the mixture was kept at 50°C overnight. It was evaporated at reduced pressure and recrystallized from water to yield 46 g of the title compound as white leaves, m.p. 63-65 ^: C.

NMR: ³ C in CD- _j OD; 63.90, 70.72, 71.44, 104.70, 116.56, 120.07, 135.09, 163.86 ppm.

c) (2S)-l-(4-cyanophenoxy)-3-n>ethanesulfonyloxy propan-2-ol

57.2 g of (2R)-3-(4 cyanophenoxy)propane-l ,2-diol was dissolved in dry pyridine, (300 ml) and treated dropwise with ethanesulfonyl chloride, (20.7 ml), at -10 ^C C. The reaction mixture was kept at 5 ^C C overnight, evaporated at reduced pressure and poured on ice and 2 M hydrochloric acid. The solid precipitate was recrystallized three times from methane!

to yield 12.3 g of the title compound, m.p. 119-121°C, (θrjl° + 9-7° (c 1.0, CH ₃ 0H).

NMR: ¹³ C in CD ₃ 0D; 37.26, 68.77, 69.92, 71.76, 105.19, 116.65, 119.99, 135.19, 163.55 ppm.

d) 4-f3-[ethyl[3-(propylthio)propyl]amino]-2(R)-hydroxy-propoxy ] benzonitrile

11.7 g of (2S)-l-(4-cyanophenoxy)-3-methanesulfonyloxy propane-2-ol, was stirred and refluxed overnight with ethyl (3-propylthio)propylamine (13.9 g), potassium carbonate (12.6 g) and acetonitrile (100 ml). Filtration and evaporation gave 21.5 g of crude product which was distributed between ether and 2 M hydrochloric acid. The aqueous layer was extracted three times with dichloromethane, in which it was present as an ion pair. Evaporation and distribution between ether and 1 M sodium hydroxide yielded the free base in the ether layer. Chromatography over silica using methanol-dichloromethane 5:95 as mobile phase gave 10.3 g of the title compound as a colourless oil, [ ] ² _D ° - 24,2° (c 1.0, CH ₃ 0H).

NMR: ¹³ C in CDC1 ₃ ; 11.53, 13.32, 22.76, 26.92, 29.71, 34.20, 47.56, 52.38, 56.20, 65.82, 70.53, 103.97, 115.17, 118.95, 133.98, 161.95 ppm.

Example 7

4-f 3- ethylj _, 3- (propyl sulf inyl) propyl] aminoj -2(R)-hydroxypropoxyj benzonitrile

Oxidation of 4- [ 3- ( _. ethyl.3-(propylthιo)propylj amino; -2(R)-hydroxy 5 propoxyjbensonitrile with m-chloroperbenzoic acid was carried out as described for the racemate in example 2. (*) ° ~ ¹⁸ - ⁶ ° - ^c 1-°» ^CH 3θH)

NMR: ¹³ C in CDC1 ₃ ; 11.35, 11.47, 13.30, 16.24, 20.47, 20.62, 47.59, 47.63, 49.83, 50.12, 52.30, 52.57, 54.53, 54.66, 56.28, 56.31, 66.13, 0 70.52, 70.60, 104.08, 115.24, 119.02, 133.85, 162.0 ppm.

Example 8

5 4-[3-'ethyl ^' ,3-(propylthio)propyl, amino. -2(S)-hydroxypropoxy -benzonitrile

The title compound was prepared in analogy with the method described in example 6. . ° + 24.0 ^: (C 1.0, CH ₃ QH)

NMR: ¹³ C in CDC1 ₃ ; 11.52, 13.27, 22.74, 26.93, 29.70, 34.19, 47.58, 52.40, 56.22, 65.85, 70.54, 103.96, 115.16, 118.89, 133.72, 161.95 ppm.

Example 9

4-[3-[ethyU3-(propylsulfiny1)propyl)amino;-2(S)-hydroxypr opoxyj' -benzonitrile

The title compound was prepared in analogy with method described in example 7 and example 2. (< jl° + 18.0° (C 1.0, CHgOH).

NMR: ¹³ C in CDC1 ₃ ; 11.31, 11.43, 13.26, 16.18, 20.41, 20.57, 47.53, 47.58, 49.8, 50.08, 52.26, 52.53, 54.48, 54.61, 56.22, 56.24, 66.09, 70.48, 70.57, 104.0, 115.20, 118.97, 133.79, 161.96 ppm.

Example 10

_- - 1 j

4-13- ethyl.4-(ethy1thio)butylj amino; -2-hydroxypropoxyj benzonitrile

in

M

2 g of ethyl-(4-(ethylthio)buty!Jamine and 2.17 g of 4-(oxiranylmethoxy)benzonitrile were mixed in 25 ml isopropanol and refluxed over night. The mixture was evaporated and the residual oil wa dissolved in 2 M HC1. This acidic waterlayer was washed with three portions of ether and then the HCl-salt of the product was extracted as ion pair with three portions of dichloromethane. The organic layer containing the ion pair was alkalized with 2 M NaOH and the organic layer now containing the base form of the product was dried over sodiu sulfate and evaporated and purified by column chromatography. Yield:3.7 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 11.67, 14.65, 25.81, 26.31, 27.18, 31.40, 47.57,

53.16, 56.08, 65.69, 70.64, 104.03, 115.20, 118.97, 133.79, 162.01 ppm.

Example 11

4-[3-[ethyl J4-(ethylsulfinyl)butyljaminoj -2-hydroxypropoxy]benzonitrile

1.68 g of 4-^3-i ethyl ,4-(ethylthio)butyl, amino-2-hydroxypropoxy _^ -benzonitrile was oxidized by 1.1 g of m-chloroperbenzoic acid in analogy with example 2. Yield: 0.7 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 6.66, 11.52, 20.41, 26.39, 45.67, 47.75, 51.25, 53.12, 56.24, 65.85, 70.54, 115.24, 119.0, 133.84, 104.0, 162.0 ppm.

Example 12

4-(3-j (2-hydroxyethyl )J3-(propylthio)propylJaπrinoj propoxyj benzonitrile

a) 4-[3- (2-hydroxyethyl)aminoJpropoxyjbenzonitrile

A solution of 3-bromo propoxy benzonitrile (10 g) and ethanolamine

(TO g) in 2-propanol (150 ml) was refluxed for 2 hours. After overnight standing, solvent was evaporated. The residue was dissolved in aqueous HC1 (2 M) and washed with diethylether. The acidic aqueous layer was basified with sodium hydroxide solution (10 M). Extraction with ethylene chloride and evaporation of the solvent gave crude material (7.2 g). Recrystallization from di-isopropylether gave 7.0 g of the title compound with m.p. 88°C.

NMR: ¹³ C in CDC1 ₃ ; 29.15, 46.04, 51.09, 60.49, 66.38, 103.55, 115.02, 119.01, 133.74, 162.04 ppm.

b) 4-..3-. (2-hydroxyethyl) _. 3-(propylthio)propyl amino, propoxy _^ benzonitrile

A mixture of 4-: 3- (2-hydroxyethyl)amino _, propoxy benzonitrile (3 g), l-bromo-3-(propylthio)propane (2.7 g) and potassium carbonate (3.7 g) in 2-propanol (50 ml) was refluxed for 28 hours. The solvent was evaporated and the residue dissolved in aqueous HC1 (2 M) and extracted with diethylether. The aqueous layer was basified with sodium hydroxide (10 M) and extracted with methylene chloride followed by drying over sodium sulfate. Evaporation of the solvent gave a crude residue, which

was purified by column chromatography. Yield 2.6 g of the title compound as an oil.

NMR: ¹³ C in CDC1 ₃ ; 13.13, 22.61, 26.53, 26.73, 29.60, 31.04, 50.11, 52.53, 55.67, 58.66, 66.06, 103.52, 114.92, 118.80, 133.60, 161.92 ppm.

Example 13

4-f 3- f (2-hydroxyethyl ) 3-(propylsulf inyl )propylj aminoj propoxyj benzonitri le

4 g of 4- '3-- (2-hydroxyethyl)j3-(propylthio)propylj amino, propoxy, - benzonitrile was oxidized with m-chloroperbenzoic acid (2.1 g) in analogy with example 2. The yield, after column chromatography was 2.5 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 13.37, 16.28, 20.69, 26.66, 50.03, 50.42, 52.92, 54.65, 55.94, 59.09, 66.29, 103.88, 115.21, 119.12, 133.94, 162.18 ppm.

Example 14

4- 3-[ (2-hydroxyethyl ) [3-(propy1sulfonyl )propyl| aminoj propoxy; -benzonitrile

A mixture of 4- 3-[ (2-hydroxyethyl)aminoj propoxyjbenzonitrile (1.3 g), l-bromo-3-(propylsulfonyl)propane (1.3 g) and potassium carbonate

T5 (1.6 g) in acetonitrile (100 ml) was refluxed over night. Work up by conventional methods including column chromatography. Yield:0.5 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 13.00, 15.82, 19.53, 26.51, 50.03, 50.20, 52.18,

20 54.71, 55.84, 58.98, 66.18, 103.75, 115.11, 119.02, 133.87, 162.01 ppm.

Example 15

?ς 4--.3-.. (2-hydroxyethyl) ;3-(methylthio)propyl; amino ^' propoxy,benzonitrile

HI

3 g of 4- [3- (2-hydroxyethyl)aminoj -propoxy benzonitrile and 2.2 g l-bromo-3-(methylthio)propane and 3.7 g of potassium carbonate were

mixed in 50 ml isopropanol and refluxed over night. The mixture was filtrated and evaporated, and the residue was dissolved in 2 M hydrochloric acid. This acid water layer was washed twice with etner, alkalized with 10 M sodium hydroxide and extracted with three portions of dichloromethane. The combined organic layers were dried over sodiumsulfate and evaporated. The residual oil was purified by column chromatography. Yield: 1.2 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 15.60, 26.50, 26.89, 32.13, 50.47, 52.75, 55.99, 58.84, 66.30, 104.06, 115.18, 119.11, 133.98, 162.17 ppm.

Example 16

4- [3- (2-hydroxyethyl ) [ 3-(methylsulfinyl )propylJ aminoj propoxyj benzonitri le

I c Hi

1.1 g of 4-, 3- (2-hydroxyethyl) _^ 3-(methylthio)propyl„ amino. propoxy. benzonitrile was oxidized with 0.87 g of m-chloroperbenzoic acid in analogy with example 2. Yield: 0.7 g of the title compound.

NMR: ¹³ C in CDC1 ₃ ; 20.42, 26.48, 38.56, 50.28, 52.09, 52.74, 55.75, 58.94, 66.08, 103.67, 115.03, 118.98, 133.77, 161.98 ppm.

Example 17

4- [3-[methy 1 {, 3- (2-propeny 1 - 1 -th i o ) prop Tjamino -2-hydroxypropoxyJ -benzonitrile

a) 4- 13(methylamino)-2-hydroxypropoxy;-benzonitrile

The title compound was prepared in analogy with the method described in example la. mp I00-102°C

NMR ¹³ C in CDC1 ₃ ; 36.18, 53.82, 67.59, 70.88, 103.97, 115.13, 118.92, 133.79, 161.88.

b) 1-ch1oro-3(2-propeny1-1-thio)-propane.

A stirred mixture of 2-propene-l-thiol(6.8 g; 92 mmol),1-bromo-3- -chloropropane (14.5 g; 92 mmol) and potassiumcarbonate (20 g 145 mmol) in acetonitrile (50 ml) was warmed at 80°C for five minutes. Filtration and evaporation gave an oily residue. Vacuum destination at 10 mm Hg gave a fraction at 65 C. Yield: 7 g (51 %) of an colourless oil.

NMR : ¹³ C in CDCK ; 27.33 , 31 .74 , 34.45 , 43.23 , 116 ,76 , 134.03

c) 4- 3-{ methyl [3- ^" 2-propenyl-l-thio)propylj amino) -2-hydroxypropoxy; -benzonitrile .

A stirred mixture of 4- .3 methylamino)-2-hydroxypropoxy]-benzonitrile (4.12 g; 20 mmol) ,l-chloro-3(2-propenyl-l-thio)propane (3.5 g; 23 mmol sodium iodide (3.5 g; 24 mmol) and potassium carbonate (5 g; 36 mmol) acetonitrile (50 ml) was refluxed for 24 hours. Filtration and evaporation of the solvent gave a residue which was purified by flash chromatography (Si0 ₂ ; CH ₂ C1 ₂ :CH ₃ 0H (9:1). Yield: 5 g (78 %)of a colourless oil .

NMR: ¹³ C in CDC1_ ₃ ; 26.62, 28.33, 34.81, 41.97, 56.63, 59.96, 65.82, 70.52, 104.08, 115.22, 116.78, 119.00, 133.84, 134.29, 161.98.

Example 18

4- 3- ethyl.3- (2-fluoropropyDthio propyl,amino,. -2-hydroxypropoxyj- -benzonitrile

A solution of l-hydroxy-3- (2-fluoropropyl)thκ>]-propane (5.5 g, 36.1 mmol), prepared by conventional ethodes from l-hydroxy-3-thiopropane and l-bromo-2-fluoropropane, was mixed with triethyl amine(3.9 g, 39.7 mmol) in methylene chloride and was then stirred and cooled to 0°C. Methanesulfonylchloride (4.1 g, 36.1 mmol) was added during a period of 20 minutes. The solution was filtered and washed twice withsodium bicarbonate and water. The yield was 8.2 g. The mesylate was dissolved in acetonitrile (100 ml) and 4-F3-(etylamino)-2-hydroxypropoxy] -benzonitrile (8.7 g, 39.4 mmol) was added. The solution was refluxed over night. The solvent was evaporated and the residue was purified by column chromatography on silica gel. Yield: 5.75 g of the title compound.

NMR: ¹³ C in CDC1_ ₃ ; 11.46, 19.88, 20.06, 26.87, 30.58,

37.74, 37.92, 47.46, 52.19, 56.07, 65.84, 70.47, 89.52, 90.86, 103.82,

115.11, 118.84, 133.64, 161.90.

Example 19

4-Ϊ3-Lethyl _L _3- _(2-fluoropropyl)sulfiπyl7propylJamino7-2-hydroxypropoxyn -benzonitrile

A solution of 4-_3-^ethyl^_3- (2-fluoropropyl)thioj propyl_ amino} -2-hydroxypropoxyJ-benzonitrile (5,1 g 14.4 mmol) and toluene-4-sulfonic acid (2.73 g, 14.4 mmol) in ethanol (100 ml) was stirred and cooled to -15 ^; C. To the mixture was added a solution of 3-chloroperbenzonic.acid

(4.5 g, 14.4 mmoljin ethanol (10 ml). The solution was stirred at room temperature for 3 h. Solid calcium hydroxide (2.66 g, 36 mmol) was adde and the slurry was stirred for 15 h. The slurry was filtered and evaporated to give an oily residue. The residue was dissolved in 2 M hydrochloric acid and washed with diethylether. The acidic solution was treated with 2 M sodium hydroxide to pH = 12 and extracted with methylene chloride. Drying over sodium sulfate and evaporation to dryness gave an oily residue which was purified by column chromatograph on silica gel. Yield: 3.2 g of the title compound.

NMR: ¹³ C in CDCI_ ₃ ; 11.07, 11.09, 11.20, 20.11, 20.25, 20.43, 20.52,

20.62, 20.66, 20.84, 47.44, 47.50, 49.87, 50.11, 50.65, 50.92, 51.32,

52.10, 52.35, 56.12, 56.82, 56.99, 59.39, 59.55, 59.71, 66.08, 70.00,

70.44, 83.48, 83.67, 84.83, 85.01, 103.76, 115.09, 118.84, 136.48, 161.86.

Example 20

4- 13-'_ethyli3-(propylsulfinyl )propyl.amino. -2-fluoropropoxy; -benzonitrile

In methylene chloride under argon atmosphere was dissolved (diethylamino)sulfur trifluoride (2.3 g, 14.2 mmol). The solution was cooled to -70°C. To this solution was added dropwise 4-ι _. 3-;ethyl 3-(propylsulfinyl )propyl, amino,-2-hydroxypropoxyj -benzonitrile (5.0 g, 14.2 mmol) in methylene chloride (5 ml). The solution was stirred at

-70°C for 1/2 h and at room temperature for 2 h and then treated with water (50 ml) and with sodium hydroxide to pH = 11. The resulting layer were separated and the water layer was extracted with methylene chloride. The combined organic fractions were washed with water and dried over sodium sulfate. The oily residue was purified by column chromatography on silica gel. Yield: 1.0 g of the title compound.

NMR: ¹³ C in CD CL ₃ ; 11.69, 13.31, 16.21, 20.45, 20.63, 22.21, 48.31, 49.85, 49.89, 52.96, 53.05, 53.65, 53.69, 53.82, 53.86, 54.49, 54.53, 68.25, 68.28, 68.44, 68.46, 89.63, 89.70, 91.03, 91.10, 104.52, 115.08, 115.25, 118.88, 133.87, 133.94, 161.61.

Example 21

4- r3-[ethyl[3-(propy1sulfinyl)propyl; aminoj -2-hydroxypropoxyj benzonitrile, addition salt with hydrochloric acid

^{r '} 1

To a solution of 4-1.3-methyl {3-(propylsulfinyl)propylj aminoj

-2-hydroxy-propoxyJ-benzonitrile (1.06 g) in methylene chloride (3 ml) was added a saturated solution of hydrogen chloride in diethylether

(3 ml) followed by diethylether (7 ml). Solvent was decanted from the resulting oil, which was washed with diethylether (3 x 10 ml) and dried under high vacuum. Yield: 1.1 g as an oil.

NMR: ¹³ C in D ₂ 0, relative dioxane (67.4 ppm); 8.74, 9.17, 13.29, 16.67, 18.23, 18.37, 18.47, 48.01, 49.23, 49.35, 50.97, 51.10, 51.73, 53.32, 53.66, 55.30, 64.77, 64.94, 70.45, 104.01, 116.36, 120.90, 135.36, 162.58 ppm.

Example 22

4- _. 3- ethyl' 3-(propylsulfinyl)propyl.amino;-2-hydroxypropoxy; benzonitrile, addition salt with biphenyl-2,2' -diyl hydrogen phosphate

4- 3- ethyl ^-(propylsulfinyDpropyl _, amino,- -2-hydroxypropoxy -benzonitrile (0.35 g) and biphenyl-2,2'-diyl-hydrogen phosphate (0.25 g) were dissolved in methylene chloride (2 ml). Addition of diisopropylether (10 ml) gave a colourless precipitate. Solvent was decanted and the solid residue was washed with diethylether. Yield: 0.54 g (90%) of colourless crystals. M.p. 147°C.

NMR, 13 C in CDC1 ₃ ; 8.68, 13.25, 16.23, 18.14, 48.38, 48.47, 49.44,

52.50, 54.49, 54.57, 56.14, 64.36, 69.96, 104.63, 115.39, 118.93, 121.64, 124.95, 129.42, 129.71, 133.98, 149.89, 149.96, 161.40 ppm,

Example 23

r ^{Γ r} t i

4- 2-hydroxy-3-; [3(propylthio)propyljamino propoxyj-benzonitrile

A solution of 4-(oxiranylmetoxy)-benzonitrile (1.32 g, 7.5 πmol) and 3-propylthio-l-propylamine (Ig, 7.5 mmol) in acetonitrile (10 ml) was

T5 refluxed over night. The solution was evaporated and the residue was dissolved in 2 M hydrochloric acid. The acidic solution was washed with diethylether, alkalized with 10 M sodium hydroxide and extracted with etylene chloride. The solvent was evaporated and the residue was purified by column chromatography on silica gel. Yield: 1.1 g of the

20 title compound.

NMR: 13 C in CDC1. 13.26, 22.67, 29.26, 29.55, 34.09, 48.43, 51.44,

67.61, 70.63, 104.00, 115.15, 118.87, 133.78, 161.82,

25

Example 24

4-.2-hydroxy-3- _. .3(propylsu1finyDpropyl amino.propoxy -benzonitrile

c r

N

A solution of 4- 2-hydroxy-3-[ [3(propylthio)propyljamino,. propoxy, -benzonitrile (0.9 g, 2.91 mmol) and toluene-4-sulfonic acid (0.55 g, 2.91 mmol) in ethanol (20 ml) was stirred and cooled to -15°C. To this solution was added a solution of 3-chloroperbenzoic acid (0.61 g, 2.91 mmol) in ethanol (10 ml) over a period of ten minutes. The mixture was stirred at -10°C for 1/2 h and at room temperature for 3 h. Solid calcium hydroxide (0.54 g, 7.27 mmol) was added and the slurry was stirred for ten minutes, filtrated and evaporated. Yield: 0.9 g of the title compound as colourless crystals with mp:76-77°C.

NMR: ¹³ C in CDCL ₃ ; 13.42, 16.34, 23.44, 48.38, 48.15, 50.19, 51.56, 54.69, 68.68, 70.73, 104.32, 115.34, 119.077, 133.99, 162.01.

Example 25

N-ethyl-N (3-propylthio)propyljamine

To a solution of 1-propanethiol (228.5 g, 3 mol) and sodium hydroxide (0.2 g) was added acrylonitrile (167.1 g, 3.15 mol) the reaction mixture was stirred over night. Water (100 ml) was added and the organic layer was separated and dried over sodium sulfate. Evaporation gave 398 g of 3-propylthio-propionitrile. A solution of 3-propylthio-propioπitrile (194 g, 1.5 mol) in ether(100 ml) was added to a suspension of lithium aluminium hydride (60 g, 1.5 mol) in ether, conventional work up gave 158 g of 3-propylthio-propylamine. All 3-propylthio-propylamine was mixed with acetic anhydride (104 ml, 1.1 mol) and stirred for 1 h. Water (300 ml) was added and extraction with methylene chloride followed by drying over sodium sulfate and evpaoration gave 161 g of 3-propylthio- -propylacetamide. 3-propylthio-propylacetamide (133 g, 1 mol) was added to a suspension of lithium aluminium hydride (42 g, 1.1 mol) in ether. Conventional work up and destination (100°C / 12 mm Hg) yielded 113.8 g of the title compound.

NMR: ¹³ C in CDC1_ ₃ : 13.34, 15.19, 22.82, 29.87, 29.95, 34.11, 43.98, 48.69.

Example 26

N-ethyl-N l(3-propylsulfinyl )-propylJamine

s

I!

0

A solution ethyl-(3-propylthio)-propylamine (1.61 g, 10 mmol) was oxidized with 3-chloroperbenzoic acid (2.1 g, 10 mmol) in analogy with example 2. The title compound was recrystallized as hydrochloride from ethyl acetate. Yield: 1.7 g.

NMR: ¹³ C in CDCL ₃ ; 12.77, 14.68, 15.65, 22.68, 43.28, 47.77, 49.75, 53.84

Example 27

,ι

4-(3- ethyl 3-(propylsulfinyl)propyl amino.-2-hydroxypropoxy. -benzonitrile

A solution of 4-(oxiranylmetoxy)-benzonitrile (0.2 g, 1.13 mmol) and ethyl-(3-propy1sulfiny1)-propylamine (0.2 g, 1.13 nmol) in acetonitrile (8 ml) was refluxed over night. The solvent was evaporated and the residue was dissolved in hydrochloric acid, washing with ether followed by alkalizing with sodium hydroxide and extracting with methylene chloride yielded 0.33 g of the title compound.

NMR: ¹³ C in ^' cDCL ₃ ; 11.31, 11.43, 13.35, 16.30, 20.46, 20.64, 47.71, 47.76, 49.65, 50.15, 52.38, 52.86, 54.65, 54.78, 56.41 , 56.45, 66.09, 70.53, 70.61, 104.24, 115.29, 119.04, 133.92, 162.00

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 rπg of the mixture (i.e. 50 mg of 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 together with 50 g of stearic aci and 50 g of carnauba wax. The uixture thus obtained was cooled and ground to a particle size of at most 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 activ 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 1.0 ml

Formulation 6. Hard gelatine capsules

10 g of active substance was mixed with 400 g of lactose and finally 2 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 g of active substance).

Formulation H. Tablets

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

Pharmacology

Drugs which cause a delay of the repolarization process, thereby prolonging the period during which the heart is unable to respond to a new stimulus (the so called effective refractory period), are said to exert a Class III antiarrhythmic action (Vaughan Williams, 1970, 1984). This effect can be recorded as a prolongation of the action potential of myocardial cells, and can be measured directly in transme brane potential recordings or indirectly in the monophasic action potential. The compounds belonging to this invention have been studied with the latter technique.

Male guinea-pigs are anaesthetized with barbiturate and ventilated with room air under blood gas control. The heart is exposed by thoracotomy and the vagal nerves are cut. A standard electrocardiogram is recorded from skin electrodes, and a monophasic action potential (MAP) is recorded from the epicardial surface of the ventricles, usually from the left one, by a specially designed bipolar electrode, which is gently pressed against the epicardial surface or attached by use of suction pressure. A local electrocardiogram from the area of the MAP electrode is also obtained (between the peripheral electrode and reference from the skin electrodes). Arterial blood pressure is recorded via an arterial cathether in one femoral artery, and intravenous lines are used for infusion of barbiturate and test substance. Since the duration of the depolarization of the heart cells (the MAP duration) is dependent on the frequency, the evaluation of a drug effect must be made at a constant frequency. For that purpose a pacing electrode is attached to the left atrium, and the heart can be electrically stimulated at a constant frequency slightly above the normal sinus node frequency.

The monophasic action potential duration at 75% repolarization is used for primary screening.

All experiments are done under β-adrenoceptor blockade, achieved by pretreat ent with 0.5 g/kg propranolol.

The test substances are administered intravenously during 30 seconds in increasing doses at exact, predeterminated intervals and recordings are

made at exact intervals after dosing, both on a Mingograph recorder and on tape for later analysis of the signals by a custom-designed computer program. Dose-response curves are constructed for the different variables, and the doses needed to obtain 10 and 20 per cent prolongation of the MAP duration are derived by interpolation. The dose giving 20 per cent increase of the MAP duration (D ₂₀ MAP) is used as a measure of potency.

Selected compounds are subject to further testing in anaesthetized and chronically instrumented conscious dogs, in which effects on atrial and ventricular refractoriness are also recorded.

TABLE 1

D _2Q -MAP = -log dose (moles/kg) giving 20 per cent increase of the MAP duration in anaesthetized guinea-pigs (see screening method).

Change in ventricular refractoriness (VERP) in anaesthetized and conscious dogs at dose levels equivalent to D _2Q -MAP in guinea-pigs.

+ = prolonged VERP n.t. = not tested

Best mode of carrying out the invention

The compound 4-[_3- ethyl [3- (propy1sulfinyl)-propyl _j aminoj- -2-hydroxypropoxy benzonitrile and their salts, processes for preparing said compound and method employing said compound in therapy represent the best mode of carrying out the invention known to the inventors at present.