AU641670B2 - Novel cyclodextrin inclusion complexes - Google Patents

Novel cyclodextrin inclusion complexes Download PDF

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AU641670B2
AU641670B2 AU59374/90A AU5937490A AU641670B2 AU 641670 B2 AU641670 B2 AU 641670B2 AU 59374/90 A AU59374/90 A AU 59374/90A AU 5937490 A AU5937490 A AU 5937490A AU 641670 B2 AU641670 B2 AU 641670B2
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Bengt Magnus Lindstedt
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    • 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

OPt DATE 08/01/91 AOJP DATE 28/02/91 APPLN ID 59374 PCT NUMBER PCT/SE90/00436 PCr INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 90/15792 CO7C 317/28, 315/04 Al C08B 37/16, A61K 31/10 (43) International Publication Date: 27 December 1990 (27.12.90) (21) International Application Number: PCT/SE90/00436 (81) Designated States: AT, AT (European patent), AU, BB, BE (European patent), BG, BR, CA, CH, CH (European (22) International Filing Date: 19 June 1990 (19.06.90) patent), DE*, DE (European patent)*, DK, DK (European patent), ES, ES (European patent), FI, FR (European patent), GB, GB (European patent), HU, IT (Euro- Priority data: pean patent), JP, KP, KR, LK, LU, LU (European pa- 8902235-4 20 June 1989 (20.06.89) SE tent), MC, MG, MW, NL, NL (European patent), NO, RO, SD, SE, SE (European patent), SU, US.
(71) Applicant (for all designated States except US): AKTIEBO- LAGET HASSLE [SE/SE]; S-431 83 M61ndal Published With international search report.
(72) Inventor; and Inventor/Applicant (for US only) LINDSTEDT, Bengt, Magnus [SE/SE]; Torsgatan 29, S-431 38 M61ndal (SE).
(74) Agents: MIKSCHE, Gerhard et al.; Aktiebolaget Astra, Patent Department, S-151 85 Sadertilje 6 (54) Title: NOVEL CYCLODEXTRIN INCLUSION COMPLEXES 0 N S I O H
CN
(57) Abstract An inclusion complex of 4-3-[ethyl-[3-(propylsulfinyl)-propyl]amino]-2-hydroxypropoxy]-benzonitrile 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.
See back of page WO 90/15792 I PCT/SE90/00436 NOVEL CYCLODEXTRIN INCLUSION 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 ethyl-3-(propylsulfinyl -propylamino7-2-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 *ethyl(3-(propylsulfinyl)-propylfamineJ-2-hydroxypropoxyj-benzonitrile having the formula I 0 N S OH II 0
CN
which can be obtained as a stereoisomeric mixture as well as in the form of the different isomers, for instance: 4-[3-ethylD- (propylsulfinyl)propy L1amino/-2 (R)-hydrovxpropoxy]-benzonitrile, 4-f3-Lethyl3-(propylsulfinyl)-propyjamino-2 (S)-hydroxypropoxy]-benzonitrile.
WO 90/15792 PCr/SE90/00436 The gtereoisocmeric mixture as well as the above mentioned stereoisomers can be obtained by oxidizing the appropriate 4-/3-[ethyll3-(propylthio )-propylj aminoJ-2-hydroxybenzonitrile with m-chloroperbenzoic acid or analogous to netlhods 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-Zethyl3-((R*)-propylsulfinyl)propyL/aamino-2(R)hydroxypropoxy]-benzonitrilie, 4-f3-[ethylC3-((S*)-propylsulfinyl)propyl]amino]-2(R)hydroxypropoxy]-benzonitrile, 4-[3-fethyl -propylsulf inyl) propyljamino2-2 hydroxypropoxy-benzonitrile, and [ethyl73-((S*)-propylsulf inyl propyt/amino) hydroxypropoxy] -benzonitrile.
WO 90/15792 PCT/SE90/00436 According to another aspect of the inclusion complex of the present invention the cyclodextrin may be an unsubstituted cyclodextrin, i.e. ot-, p or /-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)--cyclodextrin and heptakis-( 2,6-di-0-methyl) cyclodextrin.
Examples of hydroxyethyl and hydroxypropyl cyclodextrins are hydroxyethyl-f -cyclodextrin and hydroxypropyl-/ cyclodextrin, respectively.
Preferably, the cyclodextrin is., -cyclodextrin or Ycyclodextrin.
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.
WO 90/15792 PCrSE90/004136 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 cyclode.trins 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 3 -cyclodextrin and 4- 3-Cethyl(3-(propylsulfinyl) propyl] amino -2-hydroxypropoxy -benzonitrile Solution 1 was prepared by dissolving 7.53 g 4-/3-Lethyl- 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 6$-cyclodextrin in 300 g deionized water by agitation at 70 0
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 ml cold water and freeze dried. The total vield was WO 90/15792 PCI/SE9O/00436 g and the content 4-[3-C[ethyl[f3- (propyl sulf iny1) propy IJamino]-2-hydroxypropoxy}-benzoni trule was assayed spectrophotonetrically (A=248 rim) to 14 by weight.
13Cin 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 yr-cyclodextrin and 4-[3-LethylL3- (propylsul finyl1) propyl1i7amino) -2-hydroxypropoxy-benz oni trile Solution 1 was prepared by dissolving 0.75 g 4-L3-Lethyl- [3-(propylsulf inyl) propyl, 7 ami nq7- 2-hydroxypropoxy -ben z onitrile, 0.153 g tartaric acid in 2.5 g deionized water.
Solution 2 was prepared by dissolving 4.3 g Y-cyclodextrin in 30& g water at 25 0 C. Solution I was poured into solution 2 and pH was adjusted to 8.0 with IM 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[r3- (propylsulfinyl) propylj]amino)- 2 -hydroxypropoxy] -benzo0nitrile was assayed spectrophotometrically to 15 by weight.
1Cin DMSO-d 162.57, 134.42, 119.43', 115.84, 102.90, 101.94, 81.18, 73.16, 72.84, 72.43, 71.42, 67.43, 60.2-4, 56.41, 53.32, 52.90, 52.75, 49.32, 47.90, 20.38, 16.07, 13.41, 11.88.
Exafavle 3 4-L_3-/ethy1[:3- (propylsulfinyl) propyJ aino] 2-hydroxy propoxy] -benzoni tri le WO 90/15792 PCT/SE90/00436 2.45 g of 4-f3-[ethyl/3 (propylthio)propyllamino)-2hydroxypropoxy7-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 wan added in small portions. The mixture was stirred for hour at -10 0 C and one hour at room temperature ar' 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 CDCl 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 (3-(propylsulfinyl)propyliamino/2 (R)-hydroxypropoxy2-benzonitrile Oxidation of 4-13-ethylf3-(propylthio)propyl]aminoj-2(R)hydroxypropo::vybenzonitrile with m-chloroperbenzoic acid was carried out as described for the racemate in example 3. j"20 18.60 (C 1.0, CH 3
OH).
NMR: 13C 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, 70.52, 70.60, 104.08, 115.24, 119.02, 133.85, 162.0 ppm.
ExamDle 4-f3-!ethyl/3-(propylsulfinyl)propyi/amino7-2(S)-hydroxypropoxyj-benzonitrile WO 90/15792 PCT/SE90/00436 The title compound was prepared in analogy with method described in example 4 and example 3. [J20 18.00 (C 1.0, CH 3
OH).
NMR: 13C 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-fethyl 3- -propylsulfinyl) propy L amincy-2 hydroxypropoxy-benzonitrile a) Ethyl3-(S*)-propylsulfinyl7propylamine A hot solution of 27.2 g (0.1 mol) of dioxaphosphorinane 5-dimethyl-2-hydroxy-4- (2-methoxyphenyl)-2-oxide and 17.73 g (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 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.
WO 90/15792 a PCT/SE90/00436 Extraction four times with dichloromethane yielded 2.3 g of laevorotatory amine base, arbitrarily denoted S* 1,oJ 2 0 -8.00 (c 1, CH 3
OH).
D 3 C NMR (as salt with (-)-1,3,2-dioxaphosphorinane-5,5dimethyl-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) (oxiranylmethoxy)-benzonitrile A solution of 2.71 g of (2S)-l-(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 0
C,
[/a 2 0 -14.70 (c 1, acetone).
13 NMR: C in CDC1 3 44.40, 49.71, 69.02, 104.59, 115.34, 118.95, 133.98, 161.66 ppm.
c) 4-f3-(ethyl/~3- S*)-propylsulfinyl)propy_7 amin 2 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 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.
WO 90/15792 PCT/SE90/00436 9 EXAMPLE 7 4-t3-[Cethyl[-3- -propylsulfinyl) propyljaminoj-2 hydroxypropoxy? -benzonitrile a) Ethyl -propylsulfinyl) propylamine Resolution of racemic ethyl (3-propylsulfinyl) propy±tunine with 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 Rt, has the following date: f~oil.
20 7.6 0 (c=1, CH 3 OH)
D
13CNMR (as salt with (+)-1,3,2-dioxaphosphorinane-5,5dimethyl-2-hydroxy-4- (2-methoxyphenyl) -2-oxide); in CDCl 3 10.92, 13.07, 15.93, 17.66, 19-56, 19.70, 20.52, 36.72, 36.73, 42..C9, 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) (oxiranylinethoxy) -benzonitrile From 2.7 g (2R) -1-(4-cyanophenoxy) -3-nethanesulfonyloxypropan-2-ol in analogy with example 6b was obtained 1.75 g crystalline material; m.p. 68.0Oc'# 'r 2 O 14.50 (c=l,
D
acetonia) 13CNMR in CDC1 3 44.21, 49.58, 68.90, 104.25, 115.20, 118.86, 133.80, 161.53.
c) 4 /ethyl[3- (R)-rplufiy)p pl mn)- S hydroxypropoxy2 -benzonitrile A mixture of 2.3 g of ethyl((R*)-3-propyltulfinyljpropylamine and 3.18 g of (S)-4-(oxiran~jlmethoxy) benzonitrile WO 90/15792 PCF/SE90/0436 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; [20 26.5O'.(c=1, CH 3
OH)
C NMR in CDC13: 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)propylamino7-2(R)hydroxypropoxyl-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 13.41 (c=l CH3OH).
4.27 g of an oil; fO2 0 -13.4
CH
3
H).
1C 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-/ethylf-3-((S*)-propylsulfinyl)propyl7amino7-2(S)hydroxypropoxyj-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; dO120 11.10 CH 3
OH).
13C 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 (10)

1. An inclusion complex of 4-f3-f'ethyl[3-(propylsulfinyl)- propylljaminol -2 -hydroxypropoxy..-ben zoni kr il1e having the formula I 0- N s OH0 CN 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 comiplex according to claim 1, wherein the compound of the formula I is in the form of the racemate.
3. An inclusion ccuiplex according to claim 1, wherein the compound of the formula I is in the form of one of the isomers: 4 -f3-[e thylLf'3- (propylsul finyl) propyl11amino--2 -hydroxy- propoxy]-benzonitrile
4-tJ-[ethyll3- (propylsulf inyl) propyljaminoj7-2 -hydroxy- propoxy) benzonitrile, 4-[3-/Fethyl-f3-K -propylsulf inyl) propylamino-7- 2 hydroxypropoxy.7-benzonitrile, 4-3/ehlf-S)-rplufiy)poyiaio- R hydroxypropoxyl -benzonitr ile, 4-3Zehl7-(* poyslfiy)poylaio- S hydroxypropoxy]-benzonitrile, and 4-/3-jCethylf3-9S*) -propylsulf inyl)propyl aino/ -2 hydroxypropoxy.1-benzonitrile. 4. An inclusion comiplex according to any of claims 1 3, wherein the cyclodextrin is CA, A- -Or r-cyclodextrin. WO 90/15792 PC/SE90/00436 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
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. 1
8. A method for 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 given in claim 1 with one or more cyclodextrins. 9 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. DATED this 2nd day of July, 1993 AKTIEBOLAGET HASSLE, By its Patent Attorneys, E. F. WELLINGTON CO., KBy: C S. Welling /on) LI INTERNATIONAL SEARCH REPORT International Application No PCT/SE 90/00436 I. CLASSIFICATION OF SUBJECT MATTER (if several classification symbols apply, indicate all) 6 According to International Patent Classification (IPC) or to both National Classification and IPC C 07 C 317/28, 315/04, C 08 B 37/16, A 61 K 31/10 II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System Classification Symbols C 07 C; C 08 B; A 61 K Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included in Fields Searched 8 SE,DK,FI,NO classes as above III. DOCUMENTS CONSIDERED TO BE RELEVANT 9 Category Citation of Document, 11 with indication, where appropriate, of the relevant passages 12 Relevant to Claim No. 13 P,X EP, A2, 0 322 390 1-3,7,9, 28 June 1989 page 5, lines 29-30, 33-34, 37-44; page 12, example 2; pages 14-15, example 7; pages 15-16, example 9; pages 26-27, claim 1; page 28, lines 7, 16-19, claim 7; pages 28-29, claims 8, 9; page 31, claims 17-19, 21, 22 P,X WO, Al, 8905794 (AB HASSLE) 29 June 1989, 1-3,7,9, see page 21, example 2; page 27, example 7; page 28, example 9; page 10, lines
10-12, 18, 19; claims 1, 7-9, 17-19, 21, 22 X GB, A, 1433920 (IMPERIAL CHEMICAL INDUSTRIES 1-3,7,9, LIMITED) 28 April 1976, see page 3, lines 69-71; page 1, lines
29-47; page 2, lines 96-99, claims 1, 2, 9, 10, 12, 14 Special categories of cited documents: 10 T later document published after ,he international filing date A' docunent defining the sor priority date and not In conflict with the applicalion but A co^ e R d eS t rat a ofthe a rt w h i ch is t e "t c anh th a considered to be of pair u ar relevance ited to understand the principle or theory underlying the -E earlier document but published on or after the international document of particutar relevance, the claimed invention tiling date X* document of particular relevance, the claimed invention cannot be considered novel or cannot be considered to "L doiumint which may throw doubts pn priority c iim(s or involve an inventive step which is cited to establish the publication diate of another d o icl hecam nnin itation or other special reason (as specified) document of particular nPlevance. the claimed Invention cannot be considered to involve an inventive step when the document ferring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- Sdocuther ment errin to n oral disclosure, use exhibition or nents. such combination being obvious to a person skilled other means In the art. .P document published prior to the international filing date t't W& document member of the same patent family later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this International 'earch Report 3rd September 1990 1990 -09- 1 international Searching Authority S r 0 SWEDISH PATENT OFFICE Gerd Wranne Form PCTIISAI210 (second sheet) (January 1$85) International Application No. PCT/S2- 90/00436
111. DOCUMENTS CONSID~ERED TO BE RELEVANT (CONTINUED FROM THE SECOND Category Citton of Document, with Indication, wh~ere appropriate, of the relevant passage$ Relevant to Claim No A GB, A, 1457876 (IMPERIAL CHEMICAL INDUSTRIES LTD.) November 1974, see page 12, lines 44-45; claims 1, 16, 17 EP, Al, 0094157 (TAKEDA CHEMICAL INDUSTRIES, LTD.) 16 November 1983, see claims 1, 7 1-3,7,9, 1-7,9, 1-7,9, 1-7,9, DE, Al, 2948869 (CHINOIN TERMEKEK GYARA RT) 3 see the claims GYOGYSZER ES July 1980, VEGYESZETI VEGYESZETI DE, Al, 31182,18 (CHINOIN GYOGYSZER ES TERMEKEK GYARA RT) 22 April 1982, see claims 1, 9, 17 Form PCT/ISA/21O (extra sheet) (January If International Application No. PCT/SE 90/00436 FURTHER INFORMATION CONTINUED FROM THE SECOND SHEET VfQ OBSERVATIONS WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHAULE This International search report has not btoen established in respect of certain claims under Article 17(2) for the following reasons: Claim numose..A.. because 04yi-relato subject matter not required to be searc~hed by this Authority, namely: Methods for treatment of' the human or animal body by surgery or therapy, as well as diagnostic methods /PCT Rule 39.1 (iv)7. 2.]claim numbers because Inay relate to parts of the International application triat do not comply with the prescribed raquire. menits to such an extent that no meaningtul Internationai search can be carried out, sipechifialy 1 Clairn numrrbers.......because troey are oepenet claims and are not drattea in s~o nce wtth the second and thid aentilnoes Of POT Rule 6.4(a), VIE OBSERVATIONS WHERE UNITY OF INVENTION IS LACKING2 This International Searching Authorty found multiple Inventions In this International application as follows. 1[]As all required adcillrnal search fees were timely paid by the applicant, this International search report covers mll searchable claims of the International appicAtion. 2M As only some of the required additional "earch fe~s were timely paid by the applicant, this International search report covers Only those, claims of the international applicaion for which leas were paid, specifically claims: &M No required additional search tees were timely Paid by the applicant. Conseouonily, this international search report Is rrstricteti to the invention first mentioned In the claims: it Is covered by claim numoors: ~.lAs all searchable claims could be searched wihout oflort justifying an additionlal fee, the International Searching Authority did not Invite payment at any additional tee, Remart on Protest IJThe additional sarch foes were accompaniesd by applicant's protest. No protest accompanied the payment of a~cdhlonal "earch fes. Form PCTIISA 120 (supplemental sheest C2)) I4J-rry 1985) ANN'EX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO.PCT/SE 90/00436 Th s annex lists the patent family members relating to the patent documents cited In the above-menind international search report. Thw members are as contained in the Swedish Patent Office EDP file on 90-08(-02 Thu. Gwedish Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent document Publication Patent family ublication cited In search report dale member(s) date WO-Al- 8905794 89-06-29 2824189 89-07-19 AU-D- 2824489 89-07-19 AU-D- 2910389 89-07-19 EP-A- 0322389 89-06-28 EP-A- 0322390 89-06-28 WO-A- 89/05795 89-06-29 WO-A- 89/05806 89-06-29 GB-A- 1433920 76-04-28 DE-A- 2445811 75-04-10 FR-A- 2246264 75-05-02 JP-A- 50059340 75-05-22 GB-A- 1457876 74-11-25 AT-B- 344144 78-07-10 AT-B- 345789 78-10-10 AT-B- 345791 78-10-10 AT-B- 351557 79-08-10 BE-A- 808666 74-06-14 1031362 78-05-16 CH-Ak- 605666 78-10-13 605667 78-10-13 CH-A- 605668 78-10-13 CH-A- 611876 79-06-29 CH--A- 614925 79-12-28 DE-A-C- 2362568 74-06-20 DE-A-C- 2458908 75-09-11 DE-A- 2655195 77-06-16 FR-A-B- 2210407 74-07-12 FR-A-B- 2254325 75-07-11 FR-A-B- 2333498 77-07-01 GB-A- 1455116 76-11-10 GB-A- 1550838 79-08-22 JP-C- 1250572 85-02-14 1 3P-A- 49094638 74-09-09 JP-B- 59019090 6J4-65-02 LU-A- 68997 74-02-22 LU-A- 71449 76-04-13 NL-A- 7317096 74-06-18 NL.-A- 7416114 75-06-16 SE-B-C- 408794 79-07-09 SE-B-C- 417198 81-03-02 SE-A- 7407702 75-06-13 US-A- 39ZB412 75-12-23 US-A- 4010189 77-03-01 US-A- 4083~992 78-04-11 ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO.PCT/SE 90/00436 This anneX lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the Swedish Patent Office EDP file on 90-0802 The Swedish Patent Office is in no way liable for these particulars which are merely given for the purpose of Information. Patent document Publication Patent family PufiatL cited In search report I date Imember(s) Idate GB-A- 1457876 74-11-25 US-A- 4131685 78-12-26 US-A- 4167581 79-09-11 US-A- 4171374 79-10-16 AU-D- 7620574 76-06-10 CA-A- 1034591 78-07-11 JP-A- 50089334 75-07-17 US-A- 3959369 76-05-25 US-A- 4041075 77-08-09 AT-B- 338237 77-08-10 AT-B- 343626 78-06-12 AU-D- 6330473 75-06-12 JP-C- 1383603 87-06-09 JP-A- 58222058 83-12-23 JP-B- 61048822 86-10-25 EP-Al- 0094157 83-11-16 JP-A- 59148717 84-08-25 US-A- 4659696 87-04-21 JP-A- 58189118 83-11-04 JP-A- 59021613 84-02-03 US-A- 4670419 87-06-02 [DE-Al 2948869 80-07-03 AT-B- CH-A- FR-A-B- GB-A-B- JP-B- Jp-c- JP-A- 363492 642347 2444060 2061987 1002105 1521247 55115866 81-08-10 84-04-13 80-07-11 81-05-20 89-01-13 89-09-29 80-09-06 DE-Al- 3118218 82-04-22 AT-B- 374684 84-05-25 BE-A- 888736 81-08-28 CH-A-B- 661517 87-07-31 FR-A-B- 2484252 81-12-18 JP-A- 57004914 82-01-11
AU59374/90A 1989-06-20 1990-06-19 Novel cyclodextrin inclusion complexes Ceased AU641670B2 (en)

Applications Claiming Priority (2)

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SE8902235 1989-06-20
SE8902235A SE8902235D0 (en) 1989-06-20 1989-06-20 NOVEL CYCLODEXTRIN INCLUSION COMPLEXES

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SE8902236D0 (en) * 1989-06-20 1989-06-20 Haessle Ab NOVEL POLYSTYRENESULPHONATE
DE4207922A1 (en) * 1992-03-13 1993-09-23 Pharmatech Gmbh New water-soluble inclusion complexes contg randomly substd. methyl-beta-cyclodextrin - for admin. of substances which are only sparingly soluble in water
DE4227569C1 (en) * 1992-08-20 1994-06-09 Inst Chemo Biosensorik Enzymatic determn. of inorganic phosphate - using combination of di:saccharide phosphorylase, phosphatase or maltose synthase, and glucose oxido-reductase
US7141555B2 (en) * 2000-12-19 2006-11-28 Cephalon, Inc. Modafinil compound and cyclodextrin mixtures
TWI373473B (en) * 2005-09-02 2012-10-01 Otsuka Pharma Co Ltd Anticancer agent

Citations (3)

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GB1433920A (en) * 1973-10-01 1976-04-28 Ici Ltd Alkanolamine derivatives
AU5851490A (en) * 1989-06-20 1991-01-08 Aktiebolaget Hassle Novel stereoisomers
AU5937790A (en) * 1989-06-20 1991-01-08 Aktiebolaget Hassle Novel polystyrenesulfonate

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GB1457876A (en) * 1972-12-15 1976-12-08 Ici Ltd Alkanolamine derivatives device for use in
HU177081B (en) * 1978-12-12 1981-07-28 Chinoin Gyogyszer Es Vegyeszet Process for preparing the occlusion complex of allicin with cyclodextrin
HU181703B (en) * 1980-05-09 1983-11-28 Chinoin Gyogyszer Es Vegyeszet Process for producing aqueus solutuins of water insoluble or hardly soluble vitamines, steroides, localanesthetics, prostanoides and non-steroid and antiphlogistic agents
JPS5718602A (en) * 1980-05-28 1982-01-30 Hokko Chem Ind Co Ltd Herbicide
DE3372705D1 (en) * 1982-04-30 1987-09-03 Takeda Chemical Industries Ltd Pharmaceutical composition and its use
GB8506792D0 (en) * 1985-03-15 1985-04-17 Janssen Pharmaceutica Nv Derivatives of y-cyclodextrin
SE8705150D0 (en) * 1987-12-23 1987-12-23 Haessle Ab NOVEL ANTIARRHYTHMIC AGENTS

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Publication number Priority date Publication date Assignee Title
GB1433920A (en) * 1973-10-01 1976-04-28 Ici Ltd Alkanolamine derivatives
AU5851490A (en) * 1989-06-20 1991-01-08 Aktiebolaget Hassle Novel stereoisomers
AU5937790A (en) * 1989-06-20 1991-01-08 Aktiebolaget Hassle Novel polystyrenesulfonate

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DD297404A5 (en) 1992-01-09
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KR920702674A (en) 1992-10-06
WO1990015792A1 (en) 1990-12-27
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HUT59085A (en) 1992-04-28
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SE8902235D0 (en) 1989-06-20
EP0478677A1 (en) 1992-04-08

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