NOVEL CYCLODEXTRIN INCLUSION COMPLEXES

Abstract: An inclusion complex of 4-[3-[ethyl-[3-(propylsulfinyl)-propyl]amino]-2-hydroxypropoxy]-benzon itrile having formula (I) with one or more cyclodextrins, which is useful for the treatment of cardiac arrhythmias, process for the preparation of said complex as well as the use of said complex for the preparation of medicaments with action against cardiac arrhythmias.

Description: NOVEL CYCLODEXTRIN INCLUS ION COMPLEXES Field of the invention The invention relates to novel cyclodextrin inclusion complexes, process for their preparation and their use, More particularly, the present invention relates to inclu- sion complexes of the compound 4-[3-[ ethyl/3- (propy1- sulfinyl)-propyl7amino -2-hydroxypropoxyy"-benzonitrile with cyclodextrins, their preparation and use. Background of the invention Our prior patent application PCT/SE88/00691 , filed on December 20 , 1988 and published after the filing date of this application, relates to a group of novel compounds which are useful in the treatment, acute as well as long term, of cardiac arrhythmias of diverse etiology. Among the compounds included in the group of compounds disclosed in said application is the compound 4- 3--/ " -ethyl/3- (pro- pylsulfinyl)-propyl/amine/-2-hydroxypropoxy7-benzonitrile having the formula I which can be obtained as a stereoisomeric mixture as well as in the form of the different isomers, for instance: 4-/3- ethyl£3- (propylsulfinyl) propylJamino/-2 (R) -hydroxy- propoxy/-benzonitrile, 4-/ " 3-.£ethyl/~3- (propylsulfinyl) -propyl/amino./-2 (S)-hydroxy- propoxyJ -benzonitrile. The stereoisomeric mixture as well as the above mentioned stereoiso- mers can be obtained by oxidizing the appropriate 4- 3-Zethyl(3-(pro- pyl"l_ o ' )-propy_lJ.3ininoJ-2-hydroxybenzonitrile with m-chloroper- benzoic acid or analogous to methods disclosed in the above mentioned prior patent application or the co-pending application filed the same day, our reference H 1037. The invention It has been found that the inclusion complexes of the com¬ pound of formula I with cyclodextrins are valuable new products having the same basic antiarrhythmic effect as the compound of the formula I but being in solid form whereas the compound of the formula I is an oil. Accordingly the present invention relates to an inclusion complex of the compound o.f the formula I with one or more cyclodextrins . According to one embodiment of the inclusion complex accord- ing to the invention the compound of the formula I is pre¬ sent in the form of a stereoisomeric mixture. According to another embodiment of the present invention the compound of the formula I is present in the form of one of the stereoisomers. Examples of s ereoisomers are, in addition to the two stereoisomers mentioned above, the following: 4-/ " 3-/ethyl 3-((R*) -propylsulf inyl) propyl aminq/-2 (R) - hydroxypropoxy -benzoni triie, 4-/3-/ " ethyl/ " 3-((S*) -propylsulf inyl) propyl./amino7-2 (R) - hydroxypropoxy -benzoni tr ile , 4-/ " 3- ethyl/ " 3-((R*)-propylsulfinyl)propyl7amino7-2 (S)- hydroxypropoxy./ -benzoni tr ile, and 4-/ " 3-/ethyl " 3-((S*) -propylsulfinyl) propyl aminoJ-2 (S) - hydroxypropoxy^ -benzonitrile . According to another aspect of the inclusion complex of the present invention the cyclodextrin may be an unsubsti- tuted cyclodextrin, i.e. σC-, - or ι -cyclodextrin, or a substituted cyclodextrin, e.g. a substituted cyclodextrin selected from the group consisting of methylcyclodextrins, ethylcyclodextrins, hydroxyethyl cyclodextrins and hydroxy- propyl cyclodextrins. Examples of methyl or ethyl cyclodextrins are heptakis-(3-0-methyl)-(5-cyclodextrin and heptakis- ( 2,6-di-0-methyl)-^-cyclodextrin. Examples of hydroxyethyl and hydroxypropyl cyclodextrins are hydroxyethyl-^ -cyclodextrin and hydroxypropyl--3 - cyclodextrin, respectively. Preferably, the cyclodextrin is. -* -cyclodextrin or y- cyclodextrin. The inclusion complex may be formed with one single cyclo¬ dextrin or with a mixture of at least two cyclodextrins such as those mentioned above. The molar ratio between the cyclodextrin or mixture of cyclodextrins and the compound of the. formula I will gene¬ rally be in the range of from 10:1 to 1:10, preferably above or equal to 1:1, such as 1:1 to 5:1. The present invention also relates to a process for the preparation of an inclusion complex according to the pre¬ sent invention, which process comprises reacting the com¬ pound of the formula I above with a cyclodextrin or a mixture of cyclodextrins. The reaction is typically carried out in a suitable solvent such as water. The invention further relates to a method of preventing or reducing cardiac arrhythmias in mammals, including man, which comprises administering to a host in need of such treatment an effective amount of an inclusion complex of the compound of the formula I with one or more cyclo¬ dextrins. The invention yet further relates to an inclusion complex of the compound of the formula I with one or more cyclo- dextrins for use as a medicament, particularly as an antiarrhythmic agent. The invention also relates to the use of an inclusion complex of the compound of the formula I with one or more cyclodextrins for the manufacture of medicaments with action against cardiac arrhythmias. The following non-limiting examplex further illustrate the invention. WORKING EXAMPLES Example 1 Complex of β -cyclodextrin and 4- " 3-/ " ethyl/3-(propyl¬ sulfinyl)propyl7aminq/-2-hydroxypropoxy -benzonitrile Solution 1 was prepared by dissolving 7.53 g 4-/ ~ 3-/ ~ ethyl- /3-(propylsulfinyl) propyl J 7amino7-2-hydroxypropoxv/-benzo- nitrile, 1.54 g tartaric acid in 5 g deionized water. Solution 2 was prepared by dissolving 43.0 g / 5 -cyclo¬ dextrin in 300 g deionized water by agitation at 70°C. Solution 1 was poured into solution 2. pH was raised to 8.3 by addition of 5 drops 1 M NaOH. The solution was then stirred in an ice bath for 60 minutes, and the pre¬ cipitate formed was collected by filtration, washed with 10 ml cold water and freeze dried. The total vieid was 40 g and the content 4- 3- ethyl/ * 3- (propylsulfinyl) propyl.- 7 - aminq7-2-hydroxypropoxy -benzonitrile was assayed spectro- photonetrically ( =248 nm) to 14 % by weight. 13 C in DMSO-d 6 : 162.57, 134.42, 119.43, 115.85, 102.91, 102.19, 81.80, 73.81, 72.66, 72.29, 71.43, 71.33, 67.41, 60.20, 56.43, 56.35, 53.32, 52.90, 52.76, 49.36, 47.95, 20.42, 16.07, 13.41, 11.89. Example 2 Complex of y-cyclodextrin and 4-/ " 3-Zethy1/3-(propyl¬ sulfinyl) propyiy aminoJ , -2-hydroxypropoxy7-benzonitrile Solution 1 was prepared by dissolving 0.75 g 4-/ " 3-/ " ethyl- f3-[propylsulfinyl)propy ljamino7-2-hydroxypropoxy./-benzo¬ nitrile, 0.153 g tartaric acid in 2.5 g deionized water. Solution 2 was prepared by dissolving 4.3 g y-cyclo- dextrin in 30» g water at 25°C. Solution 1 was poured into solution 2 and pH was adjusted to 8.0 with 1M NaOH. The solution was stirred in an ice-bath for 60 minutes, and the precipitate formed was collected by filtration. The total yield was 4 g and the content 4-/ * 3-/ethyl * 3- (propylsulfinyl)propyl amino./-2-hydroxypropoxy -benzo- nitrile was assayed spectrophotometrically to 15 % by weight. 13 C in DM SO -d 6 : 162.57, 134.42, 119.43, 115.84, 102.90, 101.94, 81.18, 73.16, 72.84, 72.43, 71.42, 67.43, 60.24, 56.41, 53.32, 52.90, 52.75, 49.32, 47.90, 20.38, 16.07, 13.41, 11.88 Example 3 4-/ " 3-/"ethyl/"3- (propylsulfinyl) propyl7amino./-2-hydroxy- propoxy_7-benzonitrile 2.45 g of 4- 3-/ " ethyl " 3 - (propylthio)propyl amino -2- hydroxypropoxy_7-benzonitrile and 1.4 g 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 w.-i* *** added in small portions. The mixture was stirred for 0.5 hour at -10°C and one hour at room temperature an' 1 then evaporated. The residue was dissolved in dichloro- methane 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, 56.0.9. 66.08, 70.41, 70.49, 103.76, 115.09. 118.83, 133.62, 161.88 ppm. Example 4 4-/3-/ " ethyl.Λ -(propylsulfinyl)propyl/aminσ^ (R)-hydroxy- propoxy * -benzonitrile Oxidation of 4-/3- ethyl/3- (propylthio)propyl_7amino_/-2 (R) hydroxypropoχv benzonitrile with m-chloroperbenzoic acid was carried out as described for the racemate in example 3- L J^ - 18.6° (C 1.0, CH 3 0H) . NMR: 13 C in CDC1,; 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, 70.52, 70.60, 104.08, 115.24, 119.02, 133.85, 162.0 ppm. Example 5 4-/3-/ethyl/3- (propylsulfinyl) propyl/amino.7-2 (S) -hydroxy- propoxyy-benzonitrile . The title compound was prepared in analogy with method described in example 4 and example 3. + 18.0 (C 1.0, CH 3 OH) . 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 6 4-/3-/ethyl/3-f(S*) -propylsulfinyl)propyi.7amino/-2 (R) - hydroxypropoxy_7-benzonitrile a) Ethyl 3- (S*)-propylsulfinyl7propylamine A hot solution of 27.2 g (0.1 mol) of (-)-!,3,2- diαxaphosphorinane -5,5-dimethyl-2-hydroxy-4- (2-methoxy- phenyl)-2-oxide and 17.73g(0.1 mol) of racemic ethyl (3-propyl sulfinyl) -propylamine in 750 ml of acetone and 32.5 ml of methanol was allowed to cool to room temperature, yielding 23.9 g of crytalline material. The experiment was repeated on a 0.25 mol scale, this time yielding 53.0 g of crystals. The combined crops were recrystall- ized five times from acetone-methanol, finally yielding 8.95 g of salt. A solution of 15.06 g (0.0392 mol) of trioctylamine in dichloromethane was shaken with 19.6 ml of 2M hydro- chloric acid. The phases were separated and the organic layer was washed with water. The organic phase, now con¬ taining trioctylammonium chloride, was stirred for 90 min. with a solution of 8.8 g.(0.0196 mol) of the above mentioned resolved salt in water. The phases were sepa- rated, and the organic layer was washed with water. The combined aqueous phases were washed with dichloromethane, and then brought to pH 11.5 with 10 M sodium hydroxide. Extraction four times with dichloromethane yielded 2.3 g of laevorotatory amine base, arbitrarily denoted S* i ^J^ 2 -8.0° (c = 1, CH 3 0H) . C NMR (as salt with (-}-1,3, 2-dioxaphosphorinane-5,5- dimethyl-2-hydroxy-4-(2-methoxyphenyl)-2-oxide) ; in CDC1..: 10.80, 12.95, 15.81, 17.55, 19.49, 19.58, 20.41, 36.59, 36.61, 42.37, 45.50, 48.73, 53.67, 54.71, 76.79, 76.83, 77.34, 109.63, 119.69, 126.42, 126.50, 128.33, 128.93, 155.83. b) (R) -4-(oxiranylmethoxy) -benzonitrile A solution of 2.71 g of (2S)-1-(4-cyanophenoxy) -3-methane- sulfonyloxypropan-2-ol in 40 ml of 1,2-dimethoxyethane was stirred with 1.0 g of powdered sodium hydroxide at room temperature for 22 h. 10 ml of saturated sodium chloride solution was added, and the mixture was extrac¬ ted twice with ether. Washing with 5 % sodium hydrogen carbonate, drying over magnesium sulfate, filtration and evaporation gave 1.76 g of crystalline material, = 1, acetone). 44.40, 49.71, 69.02, 104.59, 115.34, 118.95, 133.98, 161.66 ppm. c) 4-/3-/ethyl/3-tS*)-propylsulfinyl) propyl_7amino-2(R)- hydroxypropoxy -benzonitrue A mixture of 3 g of ethyl (3-(S*)-propylsulfinyl)propyl- amine and 3.18 g of (R) -4- (oxiranylmethoxy) -benzonitrile was refluxed for 16 h in 25 ml of isopropyl alcohol. After evaporation of the solvent, the crude product was dis¬ solved in 2 M hydrochloric acid, washed with ether, the solution brought to pH 11.5 with 2 M sodium hydroxide and extracted with dichloromethane. Evaporation of the orga- nic phase gave 6.11 g of an oil, 13 C NMR in CDC1 3 : 11.23, 13.17, 16.08, 20.46, 47.41, 49.98, 52.41, 54.46, 56.11, 66.05, 70.50, 103.80, 115.13, 118.92, 133.69, 161.92 ppm. EXAMPLE 7 4- 3-/ethyl/3- ( (R*) -propylsulfinyl)propyl7amino7~2 (S) hydroxypropoxy -benzonitrile a) Ethyl (3- (R*) -propylsulfinyl) propylamine Resolution of racemic ethyl(3-propylsulfinyl)propylamine with (+) -1,3,2-dioxaphosphorinane-5,5-dimethyl-2-hydroxy- 4- (2-methoxyphenyl) -2-oxide in analogy with example 6a gave dextrorotatory a ine base. This compound, arbitrarily denoted R*, has the following date: [cλ] 2( + 7.6 ' (c=l, CH 3 0H) 13C NMR (as salt with (+)-1,3,2-dioxaphosphorinane-5,5- dimethyl-2-hydroxy-4- (2-methoxyphenyl) -2-oxide) ; in CDC1-, 10.92, 13.07, 15.93, 17.66, 19.56, 19.70, 20.52, 36.72, 36.73, 42.48, 45.61, 48.85, 53.79, 54.82, 76.92, 76.96, 77.45, 77.49, 109.73, 119.81, 126.54, 126.62, 128.44, 129.06, 155.95. b) (S) -4- (oxiranylmethoxy) -benzonitrile From 2.7 g (2R) -1- (4-cyanophenoxy) -3-methanesulfonyloxy- propan-2-ol in analogy with example 6b was obtained 1.75 g crystailxlj-ixnnee mmaatteeriιaal±;; mm..pp.. 6o8o..0u°Ct- f/P*y_? , O 20 + 14.5° (c=l. acetone) 13 C NMR in CDC1 3 : 44.21, 49.58, 68.90, 104.25, 115.20, 118.86, 133.80, 161.53. c) 4-/ " 3-/ethyl ' 3- ( (R*) -propylsulfinyl)propyl7amino7-2 (S) • hydroxypropoxy7-benzonitrile A mixture of 2.3 g of ethyl/(R*)-3-propylsulfinyl/propyl¬ amine and 3.18 g of (S)-4-(oxiranylmethoxy) -benzonitrile in 19 ml of isopropyl alcohol was refluxed for 16 h and thereafter worked up in analogy with 6c yielding 4.1 g of an oil; fø]^° + 26.5° (c=l, CH 3 OH) 13 C NMR in CDC1 3 : 11.16, 13.05, 15,96, 20.37, 47.38, 49.87, 52.37, 54.31, 56.05, 66.10, 70.47, 103.65, 115.06, 118.78, 133.55, 161.86. EXEMPLE 8 4- " 3-/ethyl/ * 3-( (R*) -propylsulfinyl)propyl7amino7-2 (R)- hydroxypropoxy7-benzonitrile A mixture of 2.3 g of ethyl.(3-(R*) -propylsulfinyl)propyl- amine and 2.5 g of (R) -4- (oxiranylmethoxy) -benzonitrile was refluxed for 16 h in 19 ml of isopropyl alcohol in ana¬ logy with example 6c. Traditional work up procedures gave 4.27 g of an oil; fά7 ° -13.4° ' (c=l, CH 3 OH) . 13 C NMR in CDC1 3 : 11.58, 13.36, 16.29, 20.57, 47.70, 49.96, 52.41, 54.64, 56.36, 66.24, 70.63, 104.18, 115.33, 119.07, 133.91, 162.09. EXAMPLE 9 4-/3-/eth l 3-( (S*)-propylsulfinyl)propyl/amino/-2 (s)- hydroxypropoxy7-benzonitrile A mixture of 2.3 g of ethyl.(3- (S*) -propylsulfinyl) propyl- amine and 2.5 g of (S) -4- (oxiranylmethoxy) -benzonitrile in 19 ml isopropyl. alcohol was refluxed for 24 h in analogy with example 6c. Traditional work up procedures gave 3.65 g of an oil; M^° + 11.1° (c=l, CH 3 0H) . 13 C NMR in CDC1 3 : 11.56, 13.33, 16.25, 20.54, 47.71, 49.92, 52.42, 54.53, 56.31, 66.33, 70.64, 104.03, 115.33, 119.06, 133.86, 162.11.

Claims: C L A I M S 1. An inclusion complex of 4-/ " 3-/ethyl/3- (propylsulfinyl). propyl7amino7-2-hydroxypropoxy7-benzonitrile having the formula I with one or more cyclodextrins, the compound of the formula I being in the form of a stereoisomeric mixture or in the form of a pure stereoisomer thereof. 2. An inclusion complex according to claim 1, wherein the compound of the formula I is in the form of the racemate. 3. An inclusion cαπplex according to claim 1, wherein the compound of the formula I is in the form of one of the isomers: 4-/3-/ethyl 3-( ropylsulfinyl) propyl/amino7-2 (R) -hydroxy- propoxy7-benzonitrile , 4-/3- ethyl/3-(propylsulfinyl) propy Ijamino7-2 (S) -hydroxy propoxyybenzonitrile, 4- " 3-/~ethyl-/3-«R*)-propylsulfinyl) propyl amino7-2 (R) - hydroxypropoxy7-benzonitrile, 4-/3-/ethyl-/3-|S*) -propylsulfinyl) ropyl7amino7~2 (R) - hydroxypropoxy/-benzσnitrile, 4-/3-/ethyl/ * 3-((R*) -propylsulfinyl) propyl amino7-2 (S) - hydroxypropoxy7-benzonitrile, and 4-/3-/ethyl/3-((S*) -propylsulfinyl) propyl/amino/-2 (S)- hydroxypropoxy/-benzonitrile. 4. An inclusion complex according to any of claims 1 - 3, wherein the cyclodextrin is c* -, β - cr " ^-cyclodextrin 5. An inclusion complex according to any of claims 1 - 3, wherein the cyclodextrin is a substituted cyclodextrin selected from the group consisting of methyl cyclodextrins, ethyl cyclodextrins, hydroxyethyl cyclodextrins and hydroxypropyl cyclodextrins. 6. An inclusion complex according to any of claims 1 - 3, wherein the complex is formed with a mixture of at least two cyclodextrins as listed in claims 4 and 5. 7. Process for the preparation of an inclusion" complex as defined in any of claims 1 to 6, which process compri¬ ses reacting the compound of the formula I given in claim 1 with a cyclodextrin or a mixture of cyclodextrins. 8. A method for preventing or reducing cardiac arrhythmias in mammals, inclusing man, which comprises administering to a host in need of such treatment an effective amount of an inclusion complex of the compound of the formula I given in claim 1 with one or more cyclodextrins. 9. An inclusion complex of the compound of the formula I given in claim 1 with one or more cyclodextrins for use as a medicament particularly as an antiarrhythmic agent. 10. The use of an inclusion complex of the compound of the formula I given in claim 1 with one or more cyclo- dextrins for the manufacture of medicaments with action against cardiac arrhythmias.

Inventors: LINDSTEDT BENGT MAGNUS, LINDSTEDT, BENGT, MAGNUS
Applicants: HAESSLE AB, AKTIEBOLAGET HAESSLE
Application year: 1990
Main classification: C07C315
IPC codes: A61K31, A61K47, A61P9, C07C317, C08B37