NZ240805A - Alkylamino-substituted thiol, sulphinyl and sulphonyl derivatives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £40805 2408 (Patents Form 5 Priority sty Oatsfs): AS S£--£&i!icat''-on Fi'cd: f^ss: m.LQjmyJ^i.s.pjc.ml?^. ^ukSicstfon Dst®: 2-%-J^S-L- P.O. Journal, Ho: T ^.£T. rT- N.Z. No.

Under the provisions of Rogu- lotion- 23 (1) the ...Wn^fet. <Divide(1 out of NZ Patent APPlicatio° No" ; 227381) Specification has been ante-dated to 19 NEW ZEALAND / 29NQu1Q01 & .. — y 7 Initials Patents Act 1953 ££C§/Vr0 COMPLETE SPECIFICATION INTERMEDIATE COMPOUNDS FOR THE PREPARATION OF ANTIARRHYTHMIC AGENTS We, AKTIEBOLAGET HASSLE, a Swedish Company, of S-431 83 Sodertalje, Sweden do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- 408 2 Description Field of the Invention The invention described and claimed in the present divisional application relates to new intermediate compounds as hereinafter defined, which compounds are useful in the production of novel, pharmacologically active compounds that are described and claimed in New Zealand Patent Specification No. 227381. New Zealand Patent Specification No. 227381, which is the parent of the present divisional application, describes and claims said novel, pharmacologically active compounds, as well as processes for their preparation; and pharmaceutical compositions containing these compounds, with respect to. methods for their pharmacological use.

The object of the parent invention as described and claimed in said New Zealand Patent Specification No. 227381 is to provide pharmacologically active compounds which are useful in the acute as well as long term treatment of cardiac arrhythmias of diverse etiology. The new intermediate compounds of the present invention as so defined are hereinafter described with respect to their production and use, mainly by utilising the text of the parent specification for the purpose as a matter of convenience, the text of the parent specification haying been appropriately revised in the context, as set out below.

Background Art GB 1 433 920 discloses compounds of the formula -1 wherein R for instance stands for an alkyl or cycloalkyl radical or an aryl radical, R^ for instance stands for halogen, CN or NO2 radical, A stands for an alkylene radical of from 2 to 6 carbon atoms and X stands for -S-, -SO- or -S02- radical.

Those compounds are said to possess /3-adrenergic blocking activity.

GB 1 457 876 discloses among others the compounds NH~rnru // \Y_ nrW-runurH^NUrHori-UNH^Oo—</ \l {2C0CH2 0CH2CH0HCH2NHCH2CH2NHS02-(^ and (^r\y-OCH2CH0HCH2NHCH2CH2NHS02CH2CH2CH3 conh2 Those compounds are said to possess J3-adrenergic blocking activity.

Disclosure of the Invention The present invention provides new intermediate compounds of the formula: Ra (0) P III [ch2] s - s - rc wherein Ra is a straight or branched hydroxyalkyl or alkyl group containing 1-5 carbon atoms and optionally substituted by one or more fluoro atoms, Rc is a saturated or unsaturated, straight or branched alkyl group containing 1-4 carbon atoms and optionally substituted by one or more fluoro atoms, p is an integer 0, 1 or 2, and s is an integer 2, 3, 4 or 5.

The compounds of the invention are useful as intermediates for preparation of the pharmacologically active compounds identified by the general formula I in New Zealand Patent Specification No. 227381, which compounds are in turn useful for acute as well as long term treatment of cardiac arrhythmics of diverse etiology.

Examples of the intermediates of formula III are: C2H5 HN ~ Eh3 3 " S ~ C3H7 and C2H5 ^ HN - JcH^J 3 -S - C3H7 * Methods for the preparation and use of the intermediates of formula III in the production of the pharmacologically active compounds of the general formula I are set out in the following description, which has been taken from New Zealand Patent Specification No. 227381, in being the parent of the present divisional application. 2403 0 Thus, said pharmacologically active compounds provide antiarrhythmics which have less prominent side effects than existing antiarrhythmic drugs, as the compounds should for instance be free of negative inotropic effect and the compounds may even be positively inotropic, and should further separate the antiarrhythmic effect from the central nervous and gastrointestinal effects.

Said pharmacologically active compounds are characterized by the general formula: 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: Z I n is an integer 0,1 or 2 Y is [CH2] , CHOH, CH0CH3, CHNHR 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, A is a group wherein Ra is a straight or branched hydroxyalkyl or alkyl group containing 1-5 carbon atoms and optionally substituted by one or more fluoro atoms, Rc 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 .

Ra11 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. or R a" 7 408 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, allyl, propenyl, -C-CH, -CH2-C=CH and -C=CCH3.

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 - C \ - CH = C \ - CH? - C L ^CH3 nCH3 C»3 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 ch2chfch3, ch2ch2cf3, ch2cf2ch3, etc.

Alkyl groups in formula I which are substituted by hydroxy are for oh (j)h oh instance ch2-0h, ch2~ch2-0h, ch-ch3, ch-ch2-ch3, ch2-ch-ch3, ch2~ch2- oh oh oh I I I ch-ch2-ch2-ch3, ch2-ch-ch2-ch3, ch2-ch2-ch-ch3, ch2-ch2-ch2-oh.

Preferred groups of compounds of the invention are obtained when n is 1 Y is CH0H, CHF or (CH9) l ni wherein m = 1 408 ( Z is hydrogen A is "a <?>P ^ -(CH2)s -S- Rc, where Ra is CH3, C2H5, C3H7, CH2CH20H, ch2chohch3 , Rc is C2H5, C3H7, CH2CHFCH3 , 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 CHOH or (CH2) , Ra is C2H5, CH2CH20H, s is 3 , p is 1, R„ is CqH7 C 3 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-[ethyl[3-(propylthio)propylJaminoJ-2-hydroxy-propoxyJ benzonitrile, 4-[3-[ethyl[3-(propylsuIfinyl) propyl)ami no]-2-hydroxypropoxyJ -benzonitrile, 4-[3-[ethyl[3-(propylsulfonyl)propyl)amino]-2-hydroxypropoxy] -benzonitrile 4-[3-[ethyl[3-(methylsulfinyl) propyl]aminoj-2-hydroxypropoxy] -benzonitrile 3-[(4-cyanophenoxy)-N,N-diethyl-2-hydroxy-N-[3-(propyl-sulfinyl) propyl] --1-propanaminiuhi iodide 4-[3- [ethyllj-t propyl thio) propyl]amino]-2(R)-hydroxy-propoxyJ--benzonitrile 4-[3-[ethyl [3-(propylsulfinyl)propylJamino]-2(R)-hydroxy-propoxy]-benzonitrile 4-[3-[ethyl[3-(propylthio)propylJamino] -2(S)-hydroxypropoxy]benzonitrile 4-[3-[ethyl [3-(propylsulfinyl)propyl]amino] -2(S)-hydroxypropoxy]-benzonitrile 4-[3-[ethyl[4-(ethylthio)butylJamino]-2-hydroxypropoxy] benzonitrile 4-[3-[ethyl[4-(ethylsulfinyl)butyl] aminoJ-2-hydroxypropoxy]benzonitrile 4-[3-L2-hydroxyethyl )^3-( propyl thio) propyl] amino] propoxy] benzonitrile 4-[3-[(2-hydroxyethyl)[3-(propylsulfinyl)propyl]amino] propoxyj --benzonitrile 240805 4-[3-[(2-hydroxyethyI)[3-(propyIsulfonyl) propyl] amino]propoxy]-benzonitrile 4-[3-[(2-hydroxyethyl)[3-(methylthio) propyl] amino]-propoxy]-benzonitrile 4-[3-[(2-hydroxyethyl)[3-(methyIsulfinyI)propyI]amino]propoxy]-benzonitrile 4-[3-[ethyl[3-(propylsuIfinyl)propyl]amino]-2-hydroxypropoxy]-benzonitriIe, addition salt with hydrochloric acid 4-[3-[ethyl[3-(propylsulfinyl)propyl]amino]-2-hydroxypropoxy]-benzonitrile, addition salt with biphenyl-2,2'-diyl hydrogen phosphate 4-[3-[methyl [3-(2-propenyl-l-thio) propy l]amino] -2-hydroxypropoxy] -benzonitrile 4-[3-[ethyl[3-(2-fluropropyl)thio propyI]aniino]-2-hydroxypropoxy]-benzonitrile 4-[3-[ethyl[3-[(2-fluoropropyl)sulfinyI]propyl]amino]-2-hydroxypropoxy]-benzonitrile 4-[3-[ethyI[3-(propylsulfinyl)propyl]amino]-2-fluoropropoxy]-benzonitriIe More preferred compounds are 4-[3-[ethy1 [3-(propylthio)propyl]aminoj -2-hydroxy-propoxy]benzonitrile, 4-[3-[ethyl[3-(propylsulfinyl) propyl]amino! -2-hydroxypropox>J-•benzonitrile, 4- [3-[ethyl[3-(propylsulfonyl )propyl] amino] -2-hydroxypropoxyJ -benzonitrile 3- (4-cyanophenoxy)-N,N-diethyl-2-hydroxy-N-[3-(propyl-sulfinyl)propyl]" -1-propanaminium iodide 4-[3-[ethyl [ 3-(propylthio)propyl] amino)-2(R)-hydroxy-propoxyJ -benzonitrile 4-[3-[ethyl[3-(propylsulfinyl)propyl] ami noj-2(R)-hydroxy-propoxy] -benzonitrile 4~1.3-[ethyl [3-(propylthio)propyl]amino] -2(S)- hydroxypropoxy] benzonitrile 4-[3-[ethyl [3-(propylsulfinyl)propyl]amino]-2(S)-hydroxypropoxy] -benzonitrile 4-[3-[ethyl [4-(ethylthio)butyl]aminol-2-hydroxypropoxy]benzonitrile 4-[3-[ethyl[4-(ethylsulfinyl)butyl] aminoj-2-hyroxypropoxy]benzonitrile 4-[3-[(2-hydroxyethyl) [3-(propylthio)propyl]amino] propoxyjbenzonitrile 4-[ 3-[( 2-hydroxyethyl) [3- (propy 1 su If i ny 1) propyl] ami no] propoxy] -benzonitrile 4-[3-[^( 2-hydroxyethyl )[3-(propylsulfonyl) propyl] ami no] propoxyj -benzonitrile 4-[3- [ethyl (^3-[(2-f luoropropyl)thio] propyljamino] -2-hydroxypropoxy] -benzonitrile 4-[3-[ethyl[3~[(2-fluoropropyl )sulf inyl] propyl] amino) -2-hydroxypropoxy] -benzonitrile 4-[3-[ethyl[3-(propylsulfinyl)propyl]amin<3 -2-fluoropropoxyl -benzonitrile The most preferred compounds are 4-£3- [ethyl[3-(propylsulfinyl) propyl]amino] -2-hydroxypropoxy] -benzonitrile, 4- [3-[ethyl [3-(propylsulfinyl)propyl]amino)-2(R)-hydroxy-propoxy] -benzonitrile 4-(_3- [ethyl [3-(propyl sulf inyl) propyl] ami no] -2(S)-hydroxypropoxy] -benzonitrile 4-[3-[ethyl[4-(ethylsulfinyl)butyl]amino]-2-hydroxypropoxy]benzonitrile 4-j3-[(2-hydroxyethyl)[3-(propylsulfinyl)propyl] amino] propoxy] -benzonitrile 4-f3-[ethyl[3-[_(2-f luropropyl)su 1 f inyl] IpropylJamino] -2-hydroxypropoxy] -benzonitrile 4-[3-[ethyl[3-(propylsulf inyl Jpropyjjamino) -2-fluoropropoxy]-benzonitrile Particularly preferred compounds are 4-[3-[ethyl [3-(propylsulf inyl) propyl] ami no] -2-hydroxypropoxy] -benzonitrile 240805 13 4-[3-[ethyI[3-(propyIsulfinyl)propyl]amino]-2(R)-hydroxy-propoxy]-benzonitrile 4-[3-[ethyl[3-(propylsulfinyl)propyl]amino]-2(S)-hydroxypropoxy]-benzonitrile 4-[3-[(2-hydroxyethyl)[3-(propyIsuIfinyI)propyl]amino]propoxy]-benzonitriIe 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 formula I can be quarternarized with a lower alkyl group and the quarternary compounds have the same effect as the tertiary compounds.

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

Methods of preparation The parent New Zealand Patent Specification No. 227381 indicates that the pharmacologically active compounds of formula I may be obtained by any of the following methods: 14 A. The compounds of the formula 1 wherein A is (0), " W: - N - ICH0[s - S - Rc and the symbols n, Y and Z are defined as above, can be obtained by reaction of a compound of the formula Z R. 0 - (CH2)n-YCH- M-H II 0 CN wherein Ra is as defined above with a compound of the formula a L - (CH2)S - S - Rc wherein L is a leaving group, such as Br, CI, 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 triethylamine 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. 240B 0 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, Rg, Rc and s have the meaning given above, can be prepared by reaction of a compound of the formula 0 with a compound of the formula wherein Ra, Rc, s and p have the meanings given above. 16 The reaction is typically carried out in a suitable solvent such as isopropanol or N,N-dimethylforrnamide. 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 = 1 CHOH H 0, 1, 2 Ra» Rc and s having the meanings above, can be prepared by a reaction of a compound of formula 0 - CH, 0 with a compound of the formula 'j'p H2N - (CH2)S - S - Rc The reaction conditions are the same as described in method C above.

The product frosa this reaction step, having the formula (0). 0 - CHo - CH - CH.-NH I 2 OH (CH2)S is then alkylated by conventional methods by a suitable alkylating agent of a formula R -L, where L is a leaving group defined as above, to yield a 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 OH R (0) I la M P 0-(CH2) -CH-CH2-N-(CH2) -S-R where Rg, Rc> n, p and s have the meaning above can be prepared by reacting a compound of the formula 0-(CH9) -CH-CH9-0-S0,M 1 Ah where M is a methyl or a 4-methyl-phenyl residue, with a compound of the formula r (0) ra r ~| Vp H-N - H s - S - Rc III 18 The reaction is typically carried out in a suitable organic solvent such as acetonitrile or N,N-dimethylformar.iide. 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 Z 0 " (CVn " Y - CH - NH II CN wherein n is an integer 0,1 or 2 Y CHOCH 3' CHNHR 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, 19 Ra is, a straight or branched hydroxyalkyl or alkyl group containing 1-4 carbon 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 part of the invention .of New Zealand Patent Specification No. 227381.

The compounds of formula II are prepared by reaction of a compound of the formula 0 0 - (CH2Jn - CH - CH2 $ CN with a compound of the formula Ra - NH2 wherein n and R„ have the definitions given above, a 3 Other valuable intermediates are those of the present invention: Ra «"p HN - [chJ s - S - Rc III wherein Ra, Rc, s and p have the definitions given above.

Such intermediates can generally be obtained by a reaction of a compound of the formula Tp L - (CH2)s - § - Rc where L is CI,Br, I, mesyloxy or tosyloxy with an amine of the formula H2N " Ra A typical procedure in analogy with procedure A can be used. a 4 o e 05 Examples of such intermediates are '2h5 HN - |CH2J 3 - S - C3H7 and c0h 2 5 HN - [CH2] 3 -5 - C3H7 Other valuable intermediates for the preparation of the compounds of the formula I via method D are ° - (ch2)n - y - z h :h - n (0).

- M 2J s "S ~Rc CN wherein Y, Z, Rc> 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 - ch2 - ch - ch2 - nh - (ch2)3 - s - c3h? 1 oh cn and 0 - ch9 - ch - ch9 - nh 2 | z oh - (ch2)3- s - c3h7 CN 21 240 Working Examples Example 1 4-[3- [ethyl[3-(propylthio)propyl]ami no]-2-hydroxy-propoxy]-benzonitrile N a) 4- [3-(ethylamino)-2-hydroxypropoxy]-benzonitrile 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 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)-2-hydroxypropoxy -benzonitrile.

NMR: 13C in CDCI3; 14.88, 43.93, 51.28, 67.60, 70.77, 104.31, 115.26, 119.00, 133.93, 161.93 ppm b) 4-(3-[ethyl[3-(propylthio) propyl] amino]-2-hydroxypropoxy]--benzonitrile 4.7 g of 4-[3-(ethylamino)-2-hydroxypropoxy] -benzonitrile, 4.5 g of 22 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 chromatography. Yield 4.9 g of the title compound.

NMR: 13C in CDC 13; 11.44, 13.47, 22.52, 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-f3-fethyl£3-(propylsulfinyl) propyl)amino)-2-hydroxypropoxy) benzonitrile 2.45 g of 4-[3-/~ethyl[3-(propylthio)propylJamino] -2-hydroxypropoxyl-benzonitrile and 1.4 f p-toluenesulfonic acid were mixed in 50 ml of ethanol. The mixture was cooled to -10°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: 13C in CDC13; 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 23 Example 3 4- ("3- [ethyl [3-(propyl sulfonyl) propyl] amino] -2-hydroxypropoxy) --benzonitrile o c III N 7.3 g of 4-[3-[ethyl [3-(propylthio)propylJamino]-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 dichloromethane, 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: 13C in CDC 13; 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 24 2408 0 Example 4 4-[3-f ethylf3-(methylsulfinyl) propyl] amino]-2-hydroxypropoxy] -benzonitrile The title compound was prepared in analogy with the methods described in examples 1 and 2.

NMR: 13C in CDC 13; 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-(propylsulfinyl)propyl) -1-propanaminium iodide .0 g of 4-{j3-£ethyl[3-(propylsulf inyl) propylamines] -2-hydroxypropoxyJ -benzonitrile and 2.4 g ethyl iodide 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: 13C in D20; 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 4-f3-fethylC3-(propylthio)propyl3amino)-2(R)-hydroxypropoxyjbenzonitrile 26 408 0 a) (4S)-2,2-Dimethyl-4-(4-cyanophenoxy)methyl-1,3-dioxolane 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-dimethy 1 -4 - inethanesulfonyl-oxymethyl-1,3-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: 13C in CDC13; 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: 13C in CD30D; 63.90, 70.72, 71.44, 104.70, 116.56, 120.07, 135.09, 163.86 ppm. c) (2S)-l-(4-cyanophenoxy)-3-methanesulfony1oxy 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 methanesulfonyl chloride, (20.7 ml), at -10°C. The reaction mixture was kept at 5°C overnight, evaporated at reduced pressure and poured on ice and 2 M hydrochloric acid. The solid precipitate was recrystallized three times from methanol 27 2408 0 to yield 12.3 g of the title compound, m.p. 119-121°C, (ctJ20 + 9.7° (c 1.0, ch3oh). d NMR: 13C in CD3OD; 37.26, 68.77, 69.92, 71.76, 105.19, 116.65, 119.99, 5 135.19, 163.55 ppm. d) 4-[3-[ethyl [3-(propylthio)propyl] amin(^-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 nil). Filtration and evaporation gave 21.5 g of crude product which was 15 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-di chlorornethane 5:95'as 20 mobile phase gave 10.3 g of the title compound as a colourless oil, (a]2D° - 24,2° (c 1.0, ch3oh).

NMR: 13C in CDC13; 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. 28 Example 7 4-f3-Cethyl£3-(propylsulfinyl)propyl) ami no) -2(R)-hydroxypropoxy) benzonitri le Oxidation of 4-^3-^ethyl^3-(propylthio)propyl)amino)-2(R)-hydroxy propoxy)bensonitrile with m-chloroperbenzoic acid was carried out as described for the racemate in example 2. - 18.6° (C 1.0, CH^OH) NMR: 13C in CDC13; 1 1 .35, 1 1.47, 13.30, 16.24, 20.47, 20.62, 47.5.9, 47.63, 49.83, 50.12, 52.30, 52.57, 54.53, 54.66, 56.28, 56.31, 66.13, 70.52, 70.60, 104.08, 115.24, 119.02, 133.85, 162.0 ppm.

Example 8 4-^3-{ethylf3-(propylthio)propyl)amino)-2(S)-hydroxypropox^ -benzonitrile The title compound was prepared in analogy with the method described in example 6. (*)p0 + 24.0° (C 1.0, CH3qh). 29 408 0 NMR: 13C in CDC13; 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-(V^ethy1Q?-(propylsu1f iny 1)propyl) ami no) -2($)-hydroxypropoxy) ■ -benzonitrile The title compound was prepared in analogy with method described in example 7 and example 2. C0^)^ + 18.0° (c 1.0, ch^oh).

NMR: 13C in CDC13; 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 4-|V£ethy 1^4-(ethyl thio) butyl) amino) -2-hydroxypropoxy3benzonitrili 4 0 8 0 2 g of ethyl-(4-(ethylthio)butylJamine 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 was 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 sodiumsulfate and evaporated and purified by column chromatography. Yie1d:3.7 g of the title compound.

NMR: 13C in CDC13; 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 [4-( ethyl sulf inyl )butyl^aminoi)-2-hydroxypropox^) benzonitr i le 1.68 g of 4-^3-^thyl^l-(ethylthio)butyl)amino-2-hydroxypropox^ -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: 13C in CDC 13; 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. 31 Example 12 4-[3~C(2-hydroxyethyl))3-(propyl thio) propyl'}amino) propoxyj benzonitri le o Pt a) 4^ 2-hydroxyethyl)aminq)propoxy]benzonitrile A solution of 3-bromo propoxy benzonitrile (10 g) and ethanolamine (10 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" methylene chloride and evaporation of the solvent gave crude material (7.2 g). Recrystal1ization from di-isopropylether gave 7.0 g of the title compound with m.p. 88°C.

NMR: 13C in CDC13; 29.15, 46.04, 51.09, 60.49, 66.38, 103.55, 115.02, 119.01, 133.74, 162.04 ppm. b) 4- (V f( 2-hydroxyethyl )(*3- (propy 1 th io) propyl! ami no) propoxy) benzonitrile A mixture of 4-(3-£(2-hydroxyethyl)amino}propox,y£)benzonitrile (3 g), 1-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 32 was purified by column chromatography. Yield 2.6 g of the title compound as an oil.

NMR: 13C in CDC 13; 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-f3-f( 2-hydroxyethyl) (*3-( propyl sulf inyl )propy{) ami no) propoxy) benzonitrile 4 g of 4- -hydroxyethyl)^3-(propylthio)propyl] 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: 13C in CDC13; 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. 4 0 8 33 Example 14 4-f3-f( 2-hydroxyethyl)[3-(propyl sulfonyl)propyl) aminq)propoxy}--benzonitrile A mixture of 4-^3-£( 2-hydroxyethyl)amino)propoxy)benzonitrile (1.3 g), l-bromo-3-(propylsulfonyl)propane (1.3 g) and potassium carbonate (1.6 g) in acetonitrile (100 ml) was refluxed over night. Work up by conventional methods including column chromatography. Yie1d:0.5 g of the title compound.

NMR: 13C in CDC13; 13.00, 15.82, 19.53, 26.51, 50.03, 50.20, 52/18, 54.71, 55.84, 58.98, 66.18, 103.75, 115.11, 119.02, 133.87, 162.01 ppm.

Example 15 0~[(2-hydroxyethyl )£?-(methylthio)propyl^ amino)propoxy^benzonitri le \ o h- 3 g of 4-£(2-hydroxyethyl )amino) -propoxy^benzonitrile and 2.2 g l-bromo-3-(methylthio)propane and 3.7 g of potassium carbonate were 34 a 4 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 ether, 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: 13C in CDC13; 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-(methylsulf inyl)propyl)aminqjfpropoxy} benzonitrile 1.1 g of 4-{3-^(2-hydroxyethyl)^3-(methylthio)propyl)aminq) propoxyj 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: 13C in CDC13; 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-{methyl(*3-(2-propenyl-l-thio)propyl]amino -2-hydroxypropoxy) -benzonitrile a) 4-(3(methylamino)-2-hydroxypropoxy)-benzonitrile The title compound was prepared in analogy with the method described in example la. mp 100-102°C NMR 13C in CDC 13; 36.18, 53.82, 67.59, 70.88, 103.97, 115.13, 118.92, 133.79, 161.88. b) l-chloro-3(2-propenyl-l-thio)-propane.

A stirred mixture of 2-propene-l-thiol(6.8 g; 92 mmol),l-bromo-3--chloropropane (14.5 g; 92 mmol) and potassiumcarbonate (20 g; 145 mnol) 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. . 13„ , NMR: IJC in CDCl3; 27.33, 31.74, 34.45, 43.23, 116,76, 134, 03 36 c) 4-(3-f methyl(3-(2-propenyl-1-thio)propyl)amino) -2-hydroxypropoxy} -benzonitrile.

A stirred mixture of 4-£ 3-(methylamino)-2-hydroxypropoxy3-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) in acetonitrile (50 ml) was refluxed for 24 hours. Filtration and evaporation of the solvent gave a residue which was purified by flash chromatography (SiO^; CH^C^CH^OH (9:1). Yield: 5 g (78 %)of a colourless oil.

NMR: 13C in CDCI_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-(ethy1(3-£( 2-fluoropropyl)thio)propy l)amino)-2-hydroxypropoxy)--benzonitrile 2408 0 37 A solution of 1-hydroxy-3-£(2-fluoropropyl)thio}-propane (5.5 g, 36.1 ranol), prepared by conventional methodes 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-£3-(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: 13C in CDCI_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- Q- [ethyl h~ C 2-f luoropropyl) su If inylj propylamine!]-2-hydroxypropoxyJ -benzonitri le N A solution of 4-(3-fethyl^-02-f luoropropyl)thiij) propyl^amin<p -2-hydroxypropox£J-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 38 (4.5 g, 14.4 mmol)in ethanol (10 ml). The solution was stirred at room temperature for 3 h. Solid calcium hydroxide (2.66 g, 36 mmol) was added 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 arid extracted with methylene chloride. Drying over sodium sulfate and evaporation to dryness gave an oily residue which was purified by column chromatography on silica gel. Yield: 3.2 g of the title compound.

NMR: 13C in CDC1_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-(3-£ethy1^3-(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-{j3-[ethyl 3-(propylsulfinyl)propyl)amino)-2-hydroxypropoxy)-henzonitrile (5.0 g, 14.2 mmol) in methylene chloride (5 ml). The solution was stirred at 39 % 4 9 8 0 -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 layers 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: 13C 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. 40 f Example 21 (3-[ethyl £3-(propylsulfinyl)propyl}ami no}-2-hydroxypropoxy} benzonitrile, addition salt with hydrochloric acid To a so' )lution of 4-|[3-Cethyl(3-(propylsulfinyl)propyl)amino} -2-hydroxy-propoxy}-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: ^3C in D2O, 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, 15 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} ami no}-2-hydroxypropoxy} benzonitrile, addition salt with biphenyl-2,2' -diyl hydrogen phosphate 4-^3-{ethyl^-(propylsulf inyl )propyl}aminq) -2-hydroxypropoxy^ 25 -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: 13C in CDC 13; 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. 41 % 4 & Example 23 4-(2-hydroxy-3-f/3(propylthio)propylamine) propoxy)-benzonitril( A solution of 4-(oxiranylmetoxy)-benzonitrile (1.32 g, 7.5 urniol) and 3-propylthio-l-propylamine (Ig, 7.5 mmol) in acetonitrile (10 ml) was 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 metylene chloride. The solvent was evaporated and the residue was purified by column chromatography on silica gel. Yield: 1.1 g of the title compound.

NMR: 13 C in CDC 1- 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.

Example 24 . 4-[2-hydroxy-3^^3(propylsulf inyl)propyl) aminojpropoxy^-benzonitri 1( % 4 0 42 ^ Oil h (ft A solution of 4-j2-hydroxy-3-^(propylthio)propyl}amino) 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: 13C in CDCI_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)propyl]amine 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-propionitrile (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 mrn Hg) yielded 113.8 g of the title compound.

NMR: 13C in CDCL3: 13.34, 15.19, 22.82, 29.87, 29.95, 34.11, 43.98, 48.69.

Claims (7)

44 ?A Example 26 N-ethyl-N (73-propylsulfinyl)-propyl)amine 10 15 s il o 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 recrystal1ized as hydrochloride from ethyl acetate. Yield: 1.7 g. NMR: 13C in CDCL3; 12.77, 14.68, 15.65, 22.68, 43.28, 47.77, 49.75, 53.84 20 Example 27 4-(3-/*ethylf3-( propyl sulf inyl) propyl*) ami noj-2-hydroxypropoxxl -benzonitrile 25 A solution of 4-(oxiranylmetoxy)-benzonitrile (0.2 g, 1.13 mmol) and ethyl-(3-propylsulfinyl)-propylamine (0.2 g, 1.13 mmol) 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 30 chloride yielded 0.33 g of the title compound. NMR: 13C in CDCI_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 35 45 What we claim is:

1. A compound of the formula: HN - [CH2] s R a III S - R c wherein R is a straight or branched hydroxyalkyl or alkyl group containing 1-5 carbon atoms and optionally substituted by one or more fluoro atoms, Rc is a saturated or unsaturated, straight or branched alkyl group containing 1-4 carbon atoms and optionally substituted by one or more fluoro atoms, p is an integer 0, 1 or 2, and s is an integer 2, 3, 4 or 5.

2. A compound of claim 1, which compound has the formula:

3. A compound of claim 1, which compound has the formula: 0 HN - [CH2)3 -S - C3H7. 46 240805

4. A process for the preparation of a compound of any one of claims 1 to 3, which comprises the reaction of a compound of the formula: L - (CH2)S - 5 - R, where L is Cl, Br, I, mesyloxy or tosyloxy, with an amine of the formula: H-N - R £» ■ a wherein Ra, Rc, s and p have the definitions given in claim 1.

5. A compound of any one of claims 1 to 3 when obtained by the process of ciaim 4.

6. A compound according to claim 1 substantially as herein described or exemplified.

7. A process according to claim 4 substantially as .herein described or exemplified. AKTIEB By The HENRY Pe GET HASSLE Attorneys HES LTD