AU5937490A - Novel cyclodextrin inclusion complexes - Google Patents

Novel cyclodextrin inclusion complexes

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AU5937490A
AU5937490A AU59374/90A AU5937490A AU5937490A AU 5937490 A AU5937490 A AU 5937490A AU 59374/90 A AU59374/90 A AU 59374/90A AU 5937490 A AU5937490 A AU 5937490A AU 5937490 A AU5937490 A AU 5937490A
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benzonitrile
propylsulfinyl
cyclodextrins
hydroxypropoxy
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Bengt Magnus Lindstedt
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Hassle AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

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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 inclusion complexes of the compound 4-[3-[ ethyl[3-(propylsulfinyl)-propyl]amino]-2-hydroxypropoxy]-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-(propylsulfinyl)-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)propyl]amino]-2(R)-hydroxypropoxy]-benzonitrile,
4-[3-[ethyl[3-(propylsulfinyl)-propyl]amino]-2(S)-hydroxypropoxy] -benzonitrile. The stereoisomeric mixture as well as the above mentioned stereoisomers can be obtained by oxidizing the appropriate 4-[3-[ethyl[3-(propylthio)-propyl]ainino]-2-hydroxy]benzonitrile with m-chloroperbenzoic 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 compound 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 of the formula I with one or more cyclodextrins.
According to one embodiment of the inclusion complex according to the invention the compound of the formula I is present 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 stereoisomers are, in addition to the two stereoisomers mentioned above, the following: 4-[3-[ethyl[3-((R*)-propylsulfinyl)propyl]amino]-2(R)- hydroxypropoxy]-benzonitrile,
4-[3-[ethyl[3-((S*)-propylsulfinyl)propyl]amino7-2(R)- hydroxypropoxy]-benzonitrile,
4-[3-[ethyl[3-((R*)-propylsulfinyl)propyl]amino]-2(S)- hydroxypropoxy]-benzonitrile, and
4-[3-[ethyl[3-((S*)-propylsulfinyl)propyl]amino]-2(S)- hydroxypropoxy]-benzonitrile. According to another aspect of the inclusion complex of the present invention the cyclodextrin may be an unsubstituted cyclodextrin, i.e. α-, β- or ɣ-cyclodextrin, or a substituted cyclodextrin, e.g. a substituted cyclodextrin selected from the group consisting of methylcyclodextrins, ethylcyclodextrins, hydroxyethyl cyclodextrins and hydroxypropyl cyclodextrins.
Examples of methyl or ethyl cyclodextrins
are heptakis-(3-0-methyl)-(5-cyclodextrin and heptakis-( 2,6-di-0-methyl)-β-cyclodextrin.
Examples of hydroxyethyl and hydroxypropyl cyclodextrins are hydroxyethyl-β-cyclodextrin and hydroxypropyl-β- cyclodextrin, respectively.
Preferably, the cyclodextrin is β-cyclodextrin or ɣ- cyclodextrin. The inclusion complex may be formed with one single cyclodextrin 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 generally 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 present invention, which process comprises reacting the compound 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 cyclodextrins.
The invention yet further relates to an inclusion complex of the compound of the formula I with one or more cyclodextrins 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-(propylsulfinyl)propyl]amino]-2-hydroxypropoxy]-benzonitrile
Solution 1 was prepared by dissolving 7.53 g 4-[3-[ethyl[3-(propylsulfinyl)propyl]amino]-2-hydroxypropoxy]-benzonitrile, 1.54 g tartaric acid in 5 g deionized water.
Solution 2 was prepared by dissolving 43.0 g β-cyclodextrin 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 precipitate formed was collected by filtration, washed with 10 ml cold water and freeze dried. The total yield was 40 g and the content 4-[3-[ethyl[3-(propylsulfinyl)propyl]- amino]-2-hydroxypropoxy]-benzonitrile was assayed spectrophotonetrically (λ =248 nm) to 14 % by weight. 13C in DMSO-d6: 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 ɣ-cyclodextrin and 4-[3-[ethyl[3-(propylsulfinyl)propyl] amino]-2-hydroxypropoxy]-benzonitrile Solution 1 was prepared by dissolving 0.75 g 4-[3-[ethyl-[3-(propylsulfinyl)propyl]amino]-2-hydroxypropoxy]-benzonitrile, 0.153 g tartaric acid in 2.5 g deionized water. Solution 2 was prepared by dissolving 4.3 g ɣ-cyclodextrin 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]-benzonitrile was assayed spectrophotometrically to 15 % by weight.
13C in DMSO-d6: 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)propyl]amino]-2-hydroxypropoxy]-benzonitrile 2.45 g of 4-[3-[ethyl[3-(propylthio)propyl]amino]-2-hydroxypropoxy]-benzonitrile and 1.4 g p-toluenesulfonic acid were mixed in 50 ml of ethanol. The mixture was cooled to -10ºC 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 CDCl3; 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 4
4-[3-[ethyl[3-(propylsulfinyl)propyl]amino]-2(R)-hydroxypropoxy]-benzonitrile
Oxidation of 4-[3-[ethyl[3-(propylthio)propyl]amino]-2(R)hydroxypropoxy]benzonitrile with m-chloroperbenzoic acid was carried out as described for the racemate in example 3. [ α]D 20 - 18.6° (C 1.0, CH3OH).
NMR: 13C in CDCl3; 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]-2(S)-hydroxypropoxyy-benzonitrile The title compound was prepared in analogy with method described in example 4 and example 3. [α]D 20 + 18.0º
(C 1.0, CH3OH). NMR: 13C in CDCl3; 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-((S*)-propylsulfinyl)propyl]amino]-2(R)hydroxypropoxy]-benzonitrile a) Ethyl[3-(S*)-propylsulfinyl]propylamine
A hot solution of 27.2 g (0.1 mol) of (-)-1,3,2- dioxaphosphorinane-5,5-dimethyl-2-hydroxy-4-(2-methoxyphenyl)-2-oxide and 17.73g(0.1 mol) of racemic ethyl (3-propylsulfinyl)-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 recrystallized 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 hydrochloric acid. The phases were separated and the organic layer was washed with water. The organic phase, now containing 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 separated, 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*
[α]D 20 -8.0° (c = 1, CH3OH).
13C NMR (as salt with (-)-1,3,2-dioxaphosphorinane-5,5-dimethyl-2-hydroxy-4-(2-methoxyphenyl)-2-oxide); in CDCl3: 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-methanesulfonyloxypropan-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 extracted twice with ether. Washing with 5 % sodium hydrogen carbonate, drying over magnesium sulfate, filtration and evaporation gave 1.76 g of crystalline material, m.p. 67.5°C,
[α]D 20 -14.7° (c = 1, acetone).
NMR: 13C in CDCl3; 44.40, 49.71, 69.02, 104.59, 115.34, 118.95, 133.98, 161.66 ppm. c) 4-[3-[ethyl[3-((S*)-propylsulfinyl)propyl]amino]-2(R)-hydroxypropoxy]-benzonitrile
A mixture of 3 g of ethyl (3-(S*)-propylsulfinyl)propylamine 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 dissolved 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 organic phase gave 6.11 g of an oil,
13C NMR in CDCl3: 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)propyl]amino]-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 amine base. This compound, arbitrarily denoted R*, has the following date: [α]D 20 + 7.6º (c=1,
CH3OH)
13C NMR (as salt with (+)-1,3,2-dioxaphosphorinane-5,5- dimethyl-2-hydroxy-4-(2-methoxyphenyl)-2-oxide); in CDCl3:
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-methanesulfonyloxypropan-2-ol in analogy with example 6b was obtained 1.75 g crystailline material; m.p. 68.0°C; [α]D 20 + 14.5° (c=1, acetone) 13C NMR in CDCl3 : 44.21, 49.58, 68.90, 104.25, 115.20, 118.86, 133.80, 161.53. c) 4-[3-[ethyl[3-((R*)-propylsulfinyl)propyl]amino7-2(S)- hydroxypropoxy]-benzonitrile A mixture of 2.3 g of ethyl[(R*)-3-propylsulfinyl]propylamine 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; [α] D 2 0 + 26.5° (c=1, CH3OH)
13C NMR in CDCl3: 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)propyl]amino]-2(R)-hydroxypropoxy]-benzonitrile
A mixture of 2.3 g of ethyl (3-(R*)-propylsulfinyl)propylamine and 2.5 g of (R)-4-(oxiranylmethoxy)-benzonitrile was refluxed for 16 h in 19 ml of isopropyl alcohol in analogy with example 6c. Traditional work up procedures gave 4.27 g of an oil; [α]D 20 -13.4° (c=1, CH3OH). 13C NMR in CDCl3: 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-[ethyl[3-((S*)-propylsulfinyl)propyl]amino]-2(s)-hydroxypropoxy]-benzonitrile
A mixture of 2.3 g of ethyl (3-(S*)-propylsulfinyl)propylamine 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; [α]D 20 + 11.1° (c=1, CH3OH). 13C NMR in CDCl3: 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 (10)

C L A I M S
1. An inclusion complex of 4-[3-[ethyl[3-(propylsulfinyl)- propyl]amino]-2-hydroxypropoxy]-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-(propylsulfinyl)propyl]amino]-2(R)-hydroxypropoxy]-benzonitrile,
4-[3-[ethyl[3-(propylsulfinyl)propyI]amino7-2(S)-hydroxypropoxy]benzonitrile,
4-[3-[ethyl-[3-((R*)-propylsulfinyl)propyl]amino]-2(R)-hydroxypropoxy]-benzonitrile,
4-[3-[ethyl-[3-((S*)-propylsulfinyl)propyl]amino]-2(R)-hydroxypropoxy]-benzonitrile,
4-[3-[ethyl[3-((R*)-propylsulfinyl)propyl]amino]-2(S)-hydroxypropoxy]-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 α-, β - or ɣ-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 comprises 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 cyclodextrins for the manufacture of medicaments with action against cardiac arrhythmias.
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SE8705150D0 (en) * 1987-12-23 1987-12-23 Haessle Ab NOVEL ANTIARRHYTHMIC AGENTS
SE8902236D0 (en) * 1989-06-20 1989-06-20 Haessle Ab NOVEL POLYSTYRENESULPHONATE
SE8902237D0 (en) * 1989-06-20 1989-06-20 Haessle Ab NOVEL STEREOISOMERS

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU641671B2 (en) * 1989-06-20 1993-09-30 Aktiebolaget Hassle Novel polystyrenesulfonate

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GR900100458A (en) 1991-11-15
HU905542D0 (en) 1992-03-30
PT94415A (en) 1991-02-08
CA2058996A1 (en) 1990-12-21
LV10249A (en) 1994-10-20
DD297404A5 (en) 1992-01-09
LTIP1725A (en) 1995-07-25
KR920702674A (en) 1992-10-06
WO1990015792A1 (en) 1990-12-27
AU641670B2 (en) 1993-09-30
JPH04506212A (en) 1992-10-29
IE902162A1 (en) 1991-01-02
HUT59085A (en) 1992-04-28
GR1000747B (en) 1992-12-30
IE902162L (en) 1990-12-20
FI915935A0 (en) 1991-12-17
SE8902235D0 (en) 1989-06-20
EP0478677A1 (en) 1992-04-08

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