CN1281561C - Compound with base skeleton of 1,6-methylene-[10]-annulene and use thereof - Google Patents

Compound with base skeleton of 1,6-methylene-[10]-annulene and use thereof Download PDF

Info

Publication number
CN1281561C
CN1281561C CN 03116571 CN03116571A CN1281561C CN 1281561 C CN1281561 C CN 1281561C CN 03116571 CN03116571 CN 03116571 CN 03116571 A CN03116571 A CN 03116571A CN 1281561 C CN1281561 C CN 1281561C
Authority
CN
China
Prior art keywords
compound
annulene
ococh
formula
cooh
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN 03116571
Other languages
Chinese (zh)
Other versions
CN1450032A (en
Inventor
田伟生
丁凯
吴秀静
陈玲
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Organic Chemistry of CAS
Original Assignee
Shanghai Institute of Organic Chemistry of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Organic Chemistry of CAS filed Critical Shanghai Institute of Organic Chemistry of CAS
Priority to CN 03116571 priority Critical patent/CN1281561C/en
Publication of CN1450032A publication Critical patent/CN1450032A/en
Application granted granted Critical
Publication of CN1281561C publication Critical patent/CN1281561C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Abstract

The present invention relates to a compound with the basic skeleton of 1, 6-methylene-10-annulene, which has the structural formula, wherein * represents single-bond or double-bond, R<1>=H, -OR', -CHO, -COOH, -CO2Me, -CO2CH2CH3, -P(O)(OCH2CH3)2, -OCOCH(OH)CH3, -OCOCH2CH2COOH, (disclosed in the formula)-OCOCH(NH2)R<3> or OCOC(OH)CH(NHCOR<4>)C6H5; R<2>=OR', -OCH2OCH3, =O, -CHO, -COCH3, -COOH, -CO2CH3, -CO2CH2CH3, -OCOCH3, -OCOCH2CH3, (disclosed in the formula) or (disclosed in the formula), n=0 to 2, R'=C1 to C10 alkyl or cycloalkyl, C1 to C10 saturated or unsaturated acyl and C2 to C10 alkenyl, R<3>=-H, -CH3, -CH2OH, -CH(OH)CH3, -CH2C6H5, -CH2C6H5OH, -CH2CH(CH3)2, -CH(CH3)2, CHCH3(CH2CH3)2 and -CH2-CONH2 or -CH2CH2CONH2 -CH2OH, R<4>=-C6H5, C1 to C5 alkyl, and -C(CH3)=CHCH3 or -CH=CHC6H5. The compound has inhibitory activity effect on tumor cells, and can be used for being developed into novel antitumor medicine for treating lung cancer, mammary cancer and liver cancer or leukemia.

Description

A kind of have 1, compound of 6-methylene radical-[10]-annulene basic framework and uses thereof
Technical field
This patent relates to and a kind ofly has 1, compound of 6-methylene radical-[10]-annulene basic framework and uses thereof.This compounds has been synthesized in the carbonium ion rearrangement reaction of using the fluoro sulfonic acid fluoride to bring out efficiently.This compounds demonstrates has antitumour activity, is a kind of antineoplastic compound.
Background technology
In order to find and developing new drug, the searching with natural or non-natural compound of special bioactive, the unique novelty of chemical structure is the target that chemist, biologist and drug manufacturer are chased always.For this reason, the natural product chemistry man diligently, constantly varies one's tactics to seek from biological world and has special bioactive, the unique novel natural compounds of chemical structure; Pharmaceutical Chemist and synthetic chemistry man are then according to the synthetic recruit of the human untiring design of knowledge that has obtained.Obviously, find that the unique novel compound of chemical structure is the basis of seeking new drug.
According to some ultimate principles of medicinal design, chemosynthesis and investigate the unique novel molecular studies of some structures be seek new drug important by way of one of.Knownly contain the basic framework of naphthalene at many bioactive moleculess, by MDLComprehensive Medicinal Chemistry database retrieval, the medicine with naphthalene skeleton just has 142 kinds.Purposes relates to enzyme inhibitors, and is antitumor, antimycotic or the like.
ALRESTATIN (enzyme inhibitors) AMONAFIDE (antitumor) ALRESTATIN (antimycotic)
According to the similarity on chemical structure and the physicochemical property, 1,6-methylene radical-[10]-annulene can be considered as the peer-to-peer of naphthalene compounds.But know by literature search: after U.S. professor Vogel in 1964 has synthesized this quasi-molecule, only investigated their physico-chemical property, its biological property research has been close to blank, very little especially to the research work of its analogue.In numerous natural products, that has found at present has 1, and the natural molecule of 6-methylene radical-[10]-annulene basic framework only has Spiniferin-1 (referring to Tetra.Lett.1975 (45), 3727; J.Amer.Chem.Soc.1980 (102), 4274).Have 1 in order to understand, the biological property of the compound of 6-methylene radical-[10]-annulene basic framework, we have synthesized the dihydro product of Spiniferin-1, and (CN 02145067.6, Chem.Commun.2003 (7) 838), biological activity is investigated and is found that it has certain anti-tumor activity (CN 03115527.8).Unstable in view of natural Spiniferin-1 and its dihydro product chemical property, we also design to have synthesized has furo 1, the steroidal molecule (CN 02145067.6) of 6-methylene radical-[10]-annulene basic framework, the latter demonstrates the anti-tumor activity (CN 03115525.1) of expectation equally.
Have 1 in order further to explore, the biological property of the compound of 6-methylene radical-[10]-annulene basic framework, we have designed and have been easier to synthetic and have 1, the molecule of 6-methylene radical-[10]-annulene basic framework, bioassay shows: they are than our synthetic furo 1, and 6-methylene radical-[10]-wheel ene compound has stronger anti-tumor activity.Patent of the present invention relates to that these recruits' design is synthetic, biological activity and potential use.
Summary of the invention
The object of the invention provide a class novel have many hydrogen 1,6-methylene radical a--antineoplastic compound of [10]-annulene basic framework.
Another object of the present invention provides a kind of purposes of above-mentioned antineoplastic compound.
A class of the present invention has many hydrogen 1, the 6-methylene radical--and the compound of [10]-annulene basic framework has following structural formula:
Wherein Be expressed as singly-bound or two key, R 1=-OR ' ,-OCOCH (OH) CH 3,-OCOCH 2CH 2COOH, -OCOCH (NH 2) R 3Or OCOC (OH) CH (NHCOR 4) C 6H 5R 2=OR ' ,-OCH 2OCH 3,=O ,-CHO ,-COCH 3,-COOH ,-CO 2CH 3,-CO 2CH 2CH 3,-OCOCH 3,-OCOCH 2CH 3,,
Figure C0311657100051
Or
Figure C0311657100052
N=0-2, the thiazolinyl of the alkyl or cycloalkyl of R '=C1-10, the saturated or unsaturated acyl group of C1-C10 and C2-C10; R 3=-H ,-CH 3,-CH 2OH ,-CH (OH) CH 3,-CH 2C 6H 5,-CH 2C 6H 5OH ,-CH 2CH (CH 3) 2,-CH (CH 3) 2, CHCH 3(CH 2CH 3) 2,-CH 2-CONH 2Or-CH 2CH 2CONH 2R 4=-C 6H 5, the alkyl of C1-C5 ,-C (CH 3)=CHCH 3, or-CH=CHC 6H 5, wherein
Figure C0311657100053
Be singly-bound and R 2During=O, R 1≠-OCH 3,-OCOCH 3,-OCOC 2H 5
The synthetic method of this compounds of the present invention uses the rearrangement reaction of fluoro sulfonic acid fluoride inductive carbonium ion to synthesize this compounds (referring to CN 97106576.4) efficiently.
Compound of the present invention has the activity of inhibition to tumour cell, might be developed into the medicine of a class novel anti-tumor.
Embodiment
To help to understand the present invention by following embodiment, but not limit content of the present invention.
Synthesizing of embodiment 1 compound 2
Figure C0311657100054
Get 320mg (1mmol) compound 1, be dissolved among the anhydrous THF of 15mL, the ice-water bath cooling adds 0.22mL (1.5mmol) 1 down, 5-diaza-bicyclo [5.4.0] 11-5-alkene (1,5-Diazabicyclo[5.4.0] undec-5-ene), behind the 30min, add 0.22mL (1.5mmol) HCF 2CF 2OCF 2CF 2SO 2F continues 0 ℃ of stirring reaction.Behind the 30min, TLC (P/E=1: 1) show that raw material point disappears.Reaction solution is crossed a thick silicagel column, and THF (15mL) washing merges elutriant, adds 0.74mL (5mmol) triethylamine, the oil bath back flow reaction.Stopped reaction after 2 hours.Be spin-dried for, column chromatography gets compound 2 254mg, yield: 80%.
Compound 2:C 20H 28O 2(300.44)
IR(KBr)：v2927，2872，1669，cm -1
1H-NMR(CDCl 3，300MHz)：δ0.32(1H，d，J＝5Hz，9-H)，2.48(1H，d，J＝18Hz，cp-H)，2.85(1H，d，J＝18Hz，cp-H)，3.27(1H，t，J＝8Hz，17-H)，3.36(3H，s，17-OMe)，5.76(1H，d，J＝10Hz，1-H)，7.32(1H，d，J＝10Hz，2-H)。
EIMS：m/e?300(M).
Ultimate analysis: calculated value: C:79.96%, H:9.39%
Measured value: C:79.42%, H:9.16%
Synthesizing of embodiment 2 compounds 3
Get 100mg (0.33mmol) compound 2 and be dissolved in the 2.1mL acetate, add the 0.42mL acetic anhydride, add 125mg (0.66mmol) tosic acid, the stirring at room reaction.After 1 hour, in reaction solution, add the 5mL frozen water, stir, have light yellow solid to separate out, suction filtration, the washing filter cake, the filtrate dichloromethane extraction, extracting solution is water respectively, saturated NaHCO 3, water washing; Filter cake dissolves with methylene dichloride, washes 2 times.United extraction liquid and lysate, anhydrous sodium sulfate drying is spin-dried for, and column chromatography gets compound 3 96mg, yield: 85%.
Compound 3:C 22H 30O 2(342.48)
IR(KBr)：v2933，1747，1601cm -1
1H-NMR(CDCl 3，300MHz)：δ0.40(1H，m，9-H)，0.91(3H，s，18-Me)，2.20(3H，s，MeCO-)，2.28～2.31(2H，m，cp-H)，3.26(1H，t，J＝8Hz，17-H)，3.35(3H，s，17-OMe)，5.78(1H，s，4-H)，5.96(1H，d，J＝6Hz，1-H)，6.38(1H，d，J＝6Hz，2-H)。
EIMS：m/e?342(M)，300(M-Ac)
Ultimate analysis: calculated value: C:77.16%, H:8.83%
Measured value: C:76.69%, H:9.05%
Synthesizing of embodiment 3 compounds 5
0.5mmol substrate 4 is dissolved in the 10ml anhydrous tetrahydro furan.Ice-water bath drips down 1 of 1.5eq., 5-Diazabicyclo[5.4.0] HCF of undec-5-ene and 1.5eq. 2CF 2OCF 2CF 2SO 2F.Finish, reacted 30 minutes.Reaction solution is filtered isopyknic eluent solvent through a short and thick silicagel column.Merge washing lotion filtrate.
Triethylamine to wherein adding 5eq. is heated to backflow, react detect raw material point disappearance to TLC till.Pressure reducing and steaming solvent and triethylamine.Residue gets intermediate through column chromatography for separation.
Add 1 of 4.0eq., 5-Diazabicyclo[5.4.0] HCF of undec-5-ene and 4.0eq. 2CF 2OCF 2CF 2SO 2F filters reaction solution through a short and thick silicagel column.Eluent solvent.Merge washing lotion filtrate.The pressure reducing and steaming solvent.Residue gets product 5 through column chromatography for separation.
Compound 5 C 21H 26O 3(326.44)
1H-NMR(CDCl 3)：δ6.70(1H，d，J＝6.0Hz，1-H)，6.07(1H，d，J＝6.1Hz，2-H)，6.07(1H，s，4-H)，5.87(1H，tt，J＝52.6Hz?and?3.0Hz，HCF 2CF 2)，3.41(1H，d，J＝10.4Hz，19-Ha)，1.03(3H，s，18-CH 3)，0.88(1H，d，J＝10.2Hz，19-Hb)
Synthesizing of embodiment 4 compounds 6
Add 200mg (0.35mmol) compound 5 in exsiccant 25ml egg type bottle, the 2ml anhydrous dimethyl formamide makes it dissolving.Add 16mg (0.04eq.) tetra-triphenylphosphine palladium, 140 μ l triethylamines and 33 μ l anhydrous formic acids again.Stir, heat temperature raising to 60 ℃ reacted 1 hour.Reaction solution is cooled to room temperature, pours in the water, add 1ml2N dilute hydrochloric acid, ether extraction.Merge organic phase, washing, saturated sodium-chloride is washed, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, residue get 86mg (91%) white solid 6 through column chromatography for separation.
Compound 6 C 19H 24O (268.40)
m.p.124-125℃
[α] D 20＝+159(c0.83，CHCl 3)
IR(KBr)：v1737(C＝O)，1589cm -1(C＝C)
1H-NMR(CDCl 3)：δ6.72-6.59(2H，m，2-H?and?3-H)，5.95(2H，m，1-H?and?4-H)，3.28(1H，d，J＝10.1Hz，19-Ha)，1.03(3H，s，18-CH 3)，0.67(1H，d，J＝10.0Hz，19-Hb)，0.49(1H，m，6-H)
EIMS：m/e?268(M)，104(100％)
Ultimate analysis: calculated value. (%): C 85.03, and H 9.01
Measured value (%): C 85.20, and H 9.11
Synthesizing of embodiment 5 compounds 7
Figure C0311657100081
Add 200mg (0.35mmol) compound 5 in exsiccant 25ml egg type bottle, the 2ml anhydrous dimethyl formamide makes it dissolving.Add 20mg (0.05eq.) tetra-triphenylphosphine palladium, 2ml anhydrous methanol and 140 μ l (3eq.) triethylamines again.In reaction solution, feed carbon monoxide, be warming up to 80 ℃, reacted 3 hours.Reaction solution is poured in the water into ether extraction.Merge organic phase, washing, saturated sodium-chloride is washed, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, residue get 90mg (79%) white solid 7 through column chromatography for separation.
Compound 7 C 21H 26O 3(326.44)
m.p.172-173℃
[α] D 20＝+294(c?0.30，CHCl 3)
IR (KBr): v1737 (ketone C=O), 1703cm -1(ester C=O)
1H-NMR(CDCl 3)：δ7.68(1H，d，J＝5.9Hz，2-H)，6.57(1H，s，4-H)，6.14(1H，d，J＝5.8Hz，1-H)，3.84(3H，s，OCH 3，3.37(1H，d，J＝9.9Hz，19-Ha)，1.03(3H，s，18-CH 3)，0.65(1H，d，J＝9.9Hz，19-Hb)，0.52(1H，m，6-H)
EIMS：m/e?326(M)，311(M-CH 3)，295(M-OCH 3)，267(100％，M-CO 2CH 3)
Ultimate analysis: calculated value. (%): C 77.27, and H 8.03
Measured value (%): C 77.24, and H 8.11
Synthesizing of embodiment 6 compounds 8
Figure C0311657100091
Add 290mg (0.51mmol) compound 5 in exsiccant 25ml three-necked bottle, the 2ml anhydrous dimethyl formamide makes it dissolving.Add 23mg (0.04eq.) tetra-triphenylphosphine palladium again, 340 μ l triethylamines and 90 μ l (1.5eq.) diethyl phosphites.Be warming up to 60 ℃ under the nitrogen protection, reacted 30 hours.Reaction solution is cooled to room temperature, pours in the dilute hydrochloric acid of 2N ether extraction into.Merge organic phase, washing, saturated sodium-chloride is washed, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, residue get 173mg (89%, deduct unreacted raw material) compound 8 through column chromatography for separation.
Compound 8 C 23H 33O 4P (404.48)
IR (Film): v1739 (ketone C=O), 1583 (C=C), 1242cm -1(P=O)
1H-NMR(CDCl 3)：δ7.42(1H，dd，J HH＝5.9Hz?and?J HP＝20.4Hz，2-H)，6.28(1H，d，J HP＝7.4Hz，4-H)，6.09(1H，d，J HH＝5.1Hz，1-H)，4.19-4.01(4H，m，2xOCH 2)，3.34(1H，d，J＝9.9Hz，19-Ha)，1.33(6H，m，2xOCH 2CH 3)，1.03(3H，s，18-CH 3)，0.63(1H，d，J＝9.9Hz，19-Hb)，0.50(1H，m，6-H).
EIMS：m/e?404(M)，277(100％)
The physiologically active of embodiment 7 compounds 3
The test result of physiologically active is as shown in table 1
Table 1
Figure C0311657100092
Active control as shown in Table 2 with patent compound (CN 03115527.8)
Table 2
Testing method is as shown in table 2:
Table 2
Cell strain: A-549 people's lung cancer screening method: sulphonyl rhodamine B (sulforhodamine B, SRB) protein staining method action time: 72h Cell strain: MCF-7 human breast carcinoma screening method: sulphonyl rhodamine B (sulforhodamine B, SRB) protein staining method action time: 72h
Cell strain: BEL-7402 people's liver cancer screening method: sulphonyl rhodamine B (sulforhodamine B, SRB) protein staining method action time: 72h Cell strain: P388 mouse leukemia screening method: tetrazolium (microcultore tetrozolium, MTT) reduction method action time: 48h

Claims (3)

1. one kind has 1, and the compound of 6-methylene radical-[10]-annulene basic framework has following structural formula:
R wherein 1=-OR ' ,-OCOCH (OH) CH 3Or-OCOCH 2CH 2COOH; R 2=OR ' ,-OCH 2OCH 3,-CHO ,-COCH 3,-COOH ,-CO 2CH 3,-CO 2CH 2CH 3,-OCOCH 3,-OCOCH 2CH 3,, Or
Figure C031165710002C3
N=0-2, the thiazolinyl of the alkyl of R '=C1-10, the saturated or unsaturated acyl group of C1-C10 and C2-C10.
2. as claimed in claim 1 a kind ofly have 1, the compound of 6-methylene radical-[10]-annulene basic framework, and its feature has following structural formula:
3. as claimed in claim 1 a kind ofly have 1, and the purposes of the compound of 6-methylene radical-[10]-annulene basic framework is characterized in that being used for preparation treatment lung cancer, mammary gland, cancer liver or leukemic antitumor drug.
CN 03116571 2003-04-23 2003-04-23 Compound with base skeleton of 1,6-methylene-[10]-annulene and use thereof Expired - Fee Related CN1281561C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 03116571 CN1281561C (en) 2003-04-23 2003-04-23 Compound with base skeleton of 1,6-methylene-[10]-annulene and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN 03116571 CN1281561C (en) 2003-04-23 2003-04-23 Compound with base skeleton of 1,6-methylene-[10]-annulene and use thereof

Publications (2)

Publication Number Publication Date
CN1450032A CN1450032A (en) 2003-10-22
CN1281561C true CN1281561C (en) 2006-10-25

Family

ID=28684204

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 03116571 Expired - Fee Related CN1281561C (en) 2003-04-23 2003-04-23 Compound with base skeleton of 1,6-methylene-[10]-annulene and use thereof

Country Status (1)

Country Link
CN (1) CN1281561C (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7693508B2 (en) 2001-03-28 2010-04-06 Qualcomm Incorporated Method and apparatus for broadcast signaling in a wireless communication system
US8077679B2 (en) 2001-03-28 2011-12-13 Qualcomm Incorporated Method and apparatus for providing protocol options in a wireless communication system
US8983065B2 (en) 2001-10-09 2015-03-17 Qualcomm Incorporated Method and apparatus for security in a data processing system
US9100457B2 (en) 2001-03-28 2015-08-04 Qualcomm Incorporated Method and apparatus for transmission framing in a wireless communication system

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105026415B (en) * 2012-12-18 2019-02-01 华盛顿大学 Steroid, its prodrug and the treatment method using the compound that the 19- alkoxy -17- of neural activity replaces

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7693508B2 (en) 2001-03-28 2010-04-06 Qualcomm Incorporated Method and apparatus for broadcast signaling in a wireless communication system
US8077679B2 (en) 2001-03-28 2011-12-13 Qualcomm Incorporated Method and apparatus for providing protocol options in a wireless communication system
US9100457B2 (en) 2001-03-28 2015-08-04 Qualcomm Incorporated Method and apparatus for transmission framing in a wireless communication system
US8983065B2 (en) 2001-10-09 2015-03-17 Qualcomm Incorporated Method and apparatus for security in a data processing system

Also Published As

Publication number Publication date
CN1450032A (en) 2003-10-22

Similar Documents

Publication Publication Date Title
CN1020452C (en) Process for preparing 10-dihydro-10 deoxo-11-azaerythronolide a derivatives and their biologicalproperties
CN108117507A (en) A kind of preparation method and use of azaspiro cyclohexadienone
CN1096465C (en) Derivatives of isosorbid mononitrate, utilization as vasodilator agents with reduced tolerance
CN1281561C (en) Compound with base skeleton of 1,6-methylene-[10]-annulene and use thereof
CN112979665B (en) Griseofulvin Schmidt rearrangement derivative and preparation method thereof
CN112972478B (en) Application of griseofulvin Schmidt rearrangement derivative in preparation of antitumor drugs
CN101058598A (en) Method of synthesizing 2alpha,3alpha-epoxy-16alpha-bromo-5alpha-androsterone-17-one
CN107513050A (en) The preparation method that a kind of olefin(e) acid bromine lactonizes
DE60032827T2 (en) Process and oxazolidine intermediate for the preparation of taxanes
CN105541834A (en) A synthetic method of 2-phenyl-imidazo[1,2-a]pyridine compounds
Benedeković et al. Divergent total synthesis of crassalactones B and C and evaluation of their antiproliferative activity
DE60105314T2 (en) METHOD FOR PRODUCING TAX DERIVATIVES
Frey et al. Total synthesis of the pentacyclic diterpenoid tropone hainanolidol
CN113292629B (en) Diosgenin hydroximic acid derivative and preparation method and application thereof
CN110143927B (en) Benzimidazole chalcone derivative and preparation method and application thereof
Liu et al. A novel, stereoselective and practical protocol for the synthesis of 4β-aminopodophyllotoxins
Abe et al. Synthesis of neo-tanshinlactone Via the palladium-mediated intramolecular biaryl coupling reaction
CN104592253B (en) Novel synthesis method of temsirolimus
CN100343271C (en) C27-steroid antitumour medicine
CN1239492C (en) Medication containing 1,6-methylene-[10]-annulene-furan and steroid
CN114409723B (en) Preparation method of asiatic acid derivative with anti-tumor activity
RU2786432C2 (en) Method for obtaining nitrilo-stilbene (compounds a-104815)
CN110498796B (en) Tadalafil analogue containing sulfonyl fluoride group and synthesis method thereof
CN107353266A (en) The preparation method that a kind of olefin(e) acid bromine lactonizes
CN108863798B (en) Synthesis and biological activity evaluation of shikonin benzoyl acrylic acid carboxylic ester derivatives

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20061025

Termination date: 20120423