LV13635B - Enzymatic resolution of racemic 3-aryl-4-aminobutyric acids - Google Patents

Enzymatic resolution of racemic 3-aryl-4-aminobutyric acids Download PDF

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LV13635B
LV13635B LVP-06-28A LV060028A LV13635B LV 13635 B LV13635 B LV 13635B LV 060028 A LV060028 A LV 060028A LV 13635 B LV13635 B LV 13635B
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aryl
amino
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Grigorijs Veinbergs
Maksims Vorona
Antons Lebedevs
Aleksandrs Cernobrovijs
Ivars Kalvins
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Olainfarm As
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Priority to PCT/EP2007/051538 priority patent/WO2007096314A2/en
Priority to EA200801878A priority patent/EA014980B1/ru
Publication of LV13635B publication Critical patent/LV13635B/lv

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/001—Amines; Imines
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures

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Description

Enzymatic resolution of racemic 3-aryl-4-aminobutyric acid
Background of the invention.
The invention relates to the isolation of pure R- and 5-enantiomers from racemic 3-aryl-4aminobutyric acids by the means of selective enzymatic resolution. For example pure R- and Senantiomers of racemic 4-amino-3-phenylbutyric acid (fenibut) or 4-amino-3-pchlorophenylbutyric acid (baclofen) can be obtained by this method. It is known that only Renantiomer of fenibut is acting as mood enhancer and tranquilizer (Allan et al.. Tetrahedron, 1990, 46, No7, 2511-2524.). Similarly only Λ-enantiomer of baclofen is the bearer of antispastic activity (N. E. Bowery, Trends Pharm. Sci., 1982, 31, 411-413). Optical antipodes of these drugs: R-enantiomers of fenibut and baclofen are not only less active but even antagonistic to their R-antipodes and their presence in racemic mixture makes necessary to administer higher doses of drugs.
That is why the elaboration or effective process for the optical resolution of racemic 3-aryl-4aminobutyric acids opens way to the improvement of the target therapeutic activity of fenibut and baclofen.
Description of the prior art
Several methods of racemic 3-aryl-4-aminobutyric acids resolution into R- and R-enantiomers are documented in literature. These are mainly chromatographic separations which include tedious steps of protection and subsequent deprotection of appropriate amino acid [I. Basova et al., SU 1432051 (1986). N. Langlois et. al. Tetrahedron, 1996, 52, No 48, 15117-15126. R. D. Allan et al.. Tetrahedron, 1990, 46, No7, 2511-2524. R. E. Zeile, Synthesis, 1991, 1023.]. Direct resolution of racemic 3-aryl-4-aminobutyric acid was achieved by using columns packed with expensive chiral stationary phase [C. Vaccher, J. Chromatogr. 1991, 542, 502-507]. Some methods are represented by cumbersome preferential crystallization of diastereoisomeric salts using optically active bases cinchonidine or L-(-)-a-methylbenzylamine as resolution aģent [M. Soborcinska et al., Pol. J. Chem., 1979, 53, 435-446. A. F. Wildervanck, et al., (US 6051734, 2000.].
Optical resolution was achieved also by methods based on the combination of Chemical and enzymatic transformations [R. Chenevret, M. Desjardins, Can. J. Chem., 1994, 72, 2312-2317. R. V. Muralidhar, R. R. Chirumamilla et al., Med. Fac. Landbouww. Univ. Gent, 2001, 66, Nr 3a, 227-232]. R-Enantiomer of baclofen was also isolated from its racemic mixture by selective microbial degradation of its R-enantiomer therefore excluding the latter from utilization [W. Levadoux et al., D. US 5483765, 1998].
In general, ali mentioned methods are not convenient for large-scale production of pure enantiomeric drugs, because of ignoring technological and especially economical aspects of the availability and the cost of reaģents and materiāls.
Therefore easy and effective optical resolution method of racemic 3-aryl-4-aminobutyric acids 5 into their R- and 5-enantiomers vvas the aim of the present invention.
Summary of the invention
Present invention provides a simple process for the cheap production of optically pure R- and 5enantiomers of 3-aryl-4-aminobutyric acid. After extensive investigations vve discovered, that R10 and 5-enantiomers of 3-aryl-4-aminobutyric acid can be produced from easily available racemic ester of 3-aryl-4-aminobutyric acid 2 by its treatment vvith enzymes selected from protease family vvhich catalyze the hydrolysis of ester group and the formation of peptide bond.
Selective cyclization of 3-aryl-4-aminobutyrate 5-enantiomer in the presence of protease provided the formation of reaction mixture containing only tvvo products: 4(5)-aryl-215 pyrolidinone (35) and 3-aryl-4-aminobutyrate 2R in 7?-enantiomeric form. We found, that these compounds can be easily separated from each other by conventional extraction technique and then converted into target 3(R)-aryl-4-aminobutyric acid 17? and 3(5)-aryl-4-aminobutyric acid 15 by acidic hydrolysis (Scheme 1).
Scheme 1.
Detailed description of the invention
According to the invention, a process for the enzymatic resolution of the racemic mixture of formula 2 vvherein Ar is phenyl or/?-halo substituted phenyl, R is alkyl group and * mārks chiral carbon atom, is provided by the exposing of the racemic mixture of formula 2 to the catalyzing action of protease in its free or immobilized state in suitable aqueous or aqueous-organic cosolvent medium. These enzymes react selectively only vvith 5-enantiomer of 2 converting it into 4(5)-aryl-2-pyrrolidinone (35), but do not attach the R-enantiomer of 2. We found that obtained
3.
enantiomeric products: 4(5)-aryl-2-pyrrolidinone (30) and 3(7?)-aryl-4-aminobutyric acid ester (2R), due to their different solubility in two-phase vvater/organic soivent system at low pH can be effectively separated by extraction and then converted into enantiomeric 17? and 15” 3-aryl-4aminobutyric acids respectively by acidic hydrolysis.
The preferred reaction conditions for the enzymatic resolution of racemic esters of 3-aryl-4aminobutyric acids 2 include:
1. application of a-chymotrypsin in vvater soluble or in vvater insoluble immobilized reusable state for the resolution of 3-aryl-4-aminobutyric acid esters;
2. the preferred substituents R in 2 vvhich are represented by saturated or unsaturated alkyl group containing from 2 to 8 carbon atoms;
3. the usage of aqueous or aqueous-organic co-solvent reaction medium vvith pH betvveen 6.0-7.0;
4. reaction temperature betvveen 20-40°C;
5. the stirring or shaking of reaction mixture from 1 to 72 hours.
Thus obtained mixture of optically active 4(5)-aryl-2-pyrrolidinone (35) and 3(7?)-aryl-4aminobutyric acid ester (27?) can be separated by extraction. Any of not mixing vvith vvater organic solvents (hydrocarbons such as hexane, benzene, toluene; halogenated hydrocarbons such as chloroform, methylene chloride; esters such as ethyl acetate; ketones, ethers) may be employed for this purpose. Reaction products 27? and 3,S can be isolated from vvater and organic phases by conventional procedures such as evaporation or crystallization, if necessary. We found that 3(7?)-aryl-4-aminobutyric acid esters 27? are readily soluble in vvater in acidic conditions and can be also extracted at neutral pH 7 and isolated from organic phase by evaporation or crystallization, if necessary.
The preferred conditions for the isolation of substantially pure optically active 4(5)-aryl-225 pyrrolidinone (35) from reaction mixture include:
1. the acidification of reaction mixture till pH<2.0;
2. the extraction of 4(5)-aryl-2-pyrrolidinone (35) vvith organic soivent preferably vvith ethyl acetate, methylene chloride, toluene or benzene and the follovving evaporation of organic phase.
The preferred conditions for the isolation of substantially pure optically active 3(7?)-aryl-4aminobutyric acid ester (27?) from reaction mixture, after the elimination of 4(5)-aryl-2pyrrolidinone (35) by extraction can be performed by tvvo methods including:
1. the evaporation of vvater phase;
2. the neutralization of vvater phase till pH 7.0, the extraction of 3(7?)-aryl-4-aminobutyric acid ester (27?) vvith organic solvent preferably vvith ethyl acetate, methylene chloride, toluene or benzene and the evaporation of organic phase.
The follovving examples are illustrating but not restricting the present invention.
General procedure for the synthesis and enzymatic resolution of racemic 3-aryl-4aminobutyric acid ester 2.
Protocol 1.
A. Thionyl chloride (0.616 ml, 8.4 mM) vvas added to a cooled to -16°C mixture of 3-aryl-4aminobutyric acid 1 (5.5 mM) in 20 ml of appropriate alcohol. Obtained solution vvas boiled for 4 hours, and evaporated under reduced pressure yielding hydrochloric salt of 3aryl-4-aminobutyric acid ester 2 (98.0%-99.5% purity according to HPLC analysis).
B. Racemic 3-aryl-4-aminobutyric acid ester 2 25 mg vvas dissolved in 5 ml of 0.1 M phosphate buffer vvith pH 6.0-7.0 vvith/vvithout addition of 10% of organic co-solvent (dioxane, acetone etc.). Water soluble a-chymotrypsin’ 5 mg (or 25 mg of achymotrypsin immobilized on the suspension of SiCh (1 g) according to the procedure [K. Watanabe, G.P. Royer, Journal of Molecular Catalysis, 1983, 22, 145]) vvas added to the reaction mixture and the latter vvas stirred at 20~40°C for 72 hours. The reaction progress leading to the formation of 4(5)-aryl-2-pyrrolidinone (35) vvas monitored by HPLC.
C. After the end of enzymatic process2 the reaction mixture vvas acidified by the addition of 2N HCI to pH <2.0 and 4(5)-aryl-2-pyrrolidinone (35) vvas extracted by 3x20 ml of methylene chloride. Thus obtained organic and vvater phases vvere evaporated to dryness giving residues of 4(5)-aryl-2-pyrrolidinone (35) and 3(7?)-aryl-4-aminobutyric acid ester (27?) vvhich vvere converted in hydrochloric salts of 5- and 7?-enantiomers 15 and 17? of 3aryl-4-aminobutyric acid by their treatment in boiling 2N HCI for 20 hours and follovving evaporation of reaction mixture. Their optical purity vvas evaluated on the base of chiral HPLC analysis data3.
Protocol 2.
The enzymatic resolution of 3-aryl-4-aminobutyric acid (1) on the stages A and B vvas realized according to Protocol 1.
C. After the end of enzymatic process 2 the reaction mixture vvas acidified by the addition of 2N HCI to pH <2.0 and 4(5)-aryl-2-pyrrolidinone 35 vvas extracted by 3x20 ml of ethyl acetate and evaporated to dryness giving residue of 4(5)-aryl-2-pyrrolidinone 35. The vvater phase vvas treated vvith 5N NH4OH to pH 7 and 3(7?)-aryl-4-aminobutyric acid ester (27?) vvas extracted by 3x20 ml of ethyl acetate. Thus obtained organic pahse vvas
LV 13635 5 evaporated to dryness giving residue of 3(7?)-aryl-4-aminobutyric acid ester (27?). Both enantiomeric products were converted in hydrochloric salts of 5- and 7?-enantiomers 15 and 17? of 3-aryl-4-aminobutyric acid by their treatment in boiling 2N HCI for 20 hours and following evaporation of reaction mixture. Their optical purity was evaiuated on the base of chiral HPLC analysis data 3.
1a-chymotrypsin activity: 65-85 units/mg in the case of immobilized a-chymotrypsin the suspension of catalyst after the end of enzymatic conversion was filtered off, vvashed by distilled vvater and re-used repeatedly, if necessary.
3 mobil phase - HC104 (pH 1.0); stationarv phase - CROWNPAK CR(+)5a
The effectiveness of enzymatic resolution and the enantiomeric excess for 3-aryl-4-aminobutyric acids 7?- and 5-enantiomers obtained according the Protocol A and B are presented in the Table
1.
Table 1
The conditions of enzymatic resolution process, yields and the enantiomeric excess for 3-aryl-4aminobutyric acid 7?- and 5-enantiomers (17? and 15)
Example Nr (Protocol) R Ar Time (h) t(°C) Medium* Yield ** (%) Enantiomeric excess (%,ee)
15 17?
1(1) Et Ph 72 20-22 A 66 92 64
2(1) z'-Pr Ph 72 20-22 A 54 76 53
3(D zz-Pr Ph 72 20-22 A 78 96 76
4(1) Allyl Ph 24 20-22 A 68 74 67
5(2) Allyl Ph 72 20-22 A 86 96 84
6(1) ZZ-Bu Ph 24 20-22 A 74 90 72
7(2) zz-Bu Ph 72 20-22 A 98 98 97
8(2) Octyl Ph 72 20-22 A 62 76 60
9(1) zz-Bu p-CIPh 72 20-22 B 98 >98 >97
10(2) zz-Bu /z-CIPh 72 20-22 C 98 >98 >97
* A - phosphate buffer (pH 6.0-7.0); B - phosphate buffer/dioxane ratio 10:1; C - phosphate buffer/acetone ratio 10:2.
** reaction yield vvas calculated on the basis of decrease in the size of 3-aryl-4-aminobutyric acid ester 2 peak on HPLC chart.

Claims (3)

1. Racemiskā 3-aril-4-aminosviestskābes estera (1) sadalīšana optiskajos izomēros, kas atšķiras ar to, ka racemāta sadalīšanu veic ar proteāžu palīdzību, kuras izvēlētas no grupas, kas sastāv no α-himotripsīna, papaīna vai subtilizīna:
ROOC
ROH
Proteaze
ROOC
NH,
HOOC
HOOC
Ar
2R ©
h3o
NH,
Ar
Ar
17?
HOOC Ύ NH2 Ār
Ar ir izvēlēts no grupas, kas sastāv no fenil- vai para-halogēnfenil- un R ir izvēlēts no grupas, kas sastāv no piesātinātas vai nepiesātinātas alkilgrupas ar 2-8 oglekļa atomiem, kura atšķiras ar to, ka sastāv no sekojošiem etapiem:
10 (1) racemiskās 3-aril-4-aminosviestskābes skābes estera sastāvā esošā 3(6)-aril-4aminosviestskābes estera selektīvu ciklizāciju par 4(5)-aril-2-pirolidinonu (36);
(2) 4(S)-aril-2-pirolidinona (36) un 3(7?)-aril-4-aminosviestskābes estera (27?) atdalīšanu ar ekstrakciju pēc reakcijas maisījuma paskābināšanas līdz pH<2.0;
(3) 4(6)-aril-2-pirolidinona (36) izdalīšanu no organiskās fāzes un 3(7?)-aril-415 aminosviestskābes estera (27?) izdalīšanu no ūdens fāzes ar ietvaicēšanu vai kristalizāciju.
2. Process pēc p. 1., kas atšķiras ar to, ka proteāze ir a-himotripsīns.
3. Process pēc p. 1., kas atšķiras ar to, ka α-himotripsīns tiek lietots tā ūdenī šķīstošā formā.
4. Process pēc p. 1., kas atšķiras ar to, ka α-himotripsīns tiek lietots tā ūdenī nešķīstošā
20 imobilizētā formā.
5. Process pēc p. 1., kas atšķiras ar to, ka procesu pielieto racemiskās 3-fenil-4-aminosviestskābes esteru sadalīšanai (7?) un (6) enantiomēros.
6. Process pēc p. 1., kas atšķiras ar to, ka procesu pielieto racemiskās 3-p-hlorfenil-4aminosviestskabes esteru sadalīšanai (7?) un (6) enantiomēros.
25 7. Process pēc p. 1., kas atšķiras ar to, ka procesu pielieto racēmiskās 3-aril-4aminosviestskābes esteru, tajā skaitā zemāko un vidējo alkilesteru, kā ari nepiesātināto alkilesteru sadalīšanai enantiomēros.
8. Process pēc ρ. 1., kas atšķiras ar to, ka procesu pielieto racēmisko 3-aril-4aminosviestskābju etilesteru sadalīšanai enantiomēros.
9. Process pēc ρ. 1., kas atšķiras ar to, ka procesu pielieto racēmisko 3-aril-4aminosviestskābju κ-propilesteru sadalīšanai enantiomēros.
10. Process pēc ρ. 1., kas atšķiras ar to, ka procesu pielieto racēmisko 3-aril-4aminosviestskābju Zz<?-propilesteru sadalīšanai enantiomēros.
11. Process pēc ρ. 1., kas atšķiras ar to, ka procesu pielieto racēmisko 3-aril-4aminosviēstskābju «-butilesteru sadalīšanai enantiomēros.
12. Process pēc ρ. 1., kas atšķiras ar to, ka procesu pielieto racēmisko 3-aril-4aminosviestskābju alilesteru sadalīšanai enantiomēros.
13. Process pēc ρ. 1., kas atšķiras ar to, ka procesu pielieto racēmisko 3-aril-4aminosviestskābju oktilesteru sadalīšanai enantiomēros.
14. Process pēc ρ. 1, kas atšķiras ar to, ka etapā (1) pielietotais šķīdinātājs ir ūdens.
15. Process pēc ρ. 1, kas atšķiras ar to, ka etapā (1) pielietotais šķīdinātājs ir ūdens maisījums ar organisko šķīdinātāju, kas nejaucas vai vāji jaucas ar ūdeni un ir izvēlēts no grupas, kas sastāv no alifatiskajiem ogļūdeņražiem, aromātiskajiem ogļūdeņražiem, halogēnalkāniem, ēteriem, esteriem, ketoniem un to maisījumiem.
16. Process pēc ρ. 1., kas atšķiras ar to, ka etapu (1) veic pie 20° līdz 40°C.
17. Process pēc ρ. 1., kas atšķiras ar to, ka etapu (1) veic pie reakcijas vides pH no 6 līdz 7.
18. Process pēc ρ. 1 kas atšķiras ar to, ka etapā (3) 3(7?)-aril-4-aminosviestskābes esteri (27?) ekstrahē no ūdens fāzes pēc tās neitralizācijas līdz pH 7.
19. Process pēc ρ. 1 kas atšķiras ar to, ka etapos (2) un (3) ekstrakcijai lieto organisko šķīdinātāju, kas ir izvēlēts no grupas, kas sastāv no heksāna, benzola, toluola, hloroforma, metilēnhlorida, dihloretāna, etilacetāta, metilacetāta, dietilētera un meti 1 -/erc-butilētera.
20. Process pēc ρ. 1 kas atšķiras ar to, ka etapos (2) un (3) ekstrakcijai izmanto heksānu..
21. Process pēc ρ. 1 kas atšķiras ar to, ka etapos (2) un (3) ekstrakcijai izmanto benzolu.
22. Process pēc ρ. 1 kas atšķiras ar to, ka etapos (2) un (3) ekstrakcijai izmanto toluolu.
23. Process pēc ρ. 1 kas atšķiras ar to, ka etapos (2) un (3) ekstrakcijai izmanto hloroformu.
24. Process pēc ρ. 1 kas atšķiras ar to, ka etapos (2) un (3) ekstrakcijai izmanto metilēnhlorīdu.
25. Process pēc ρ. 1 kas atšķiras ar to, ka etapos (2) un (3) ekstrakcijai izmanto dihloretānu.
26. Process pēc ρ. 1 kas atšķiras ar to, ka etapos (2) un (3) ekstrakcijai izmanto etilacetātu.
27. Process pēc ρ. 1 kas atšķiras ar to, ka etapos (2) un (3) ekstrakcijai izmanto metilacetātu.
28. Process pēc ρ. 1 kas atšķiras ar to, ka etapos (2) un (3) ekstrakcijai izmanto dietilēteri.
29. Process pēc p. 1 kas atšķiras ar to, ka etapos (2) un (3) ekstrakcijai izmanto metil-tercbutilēteri.
30. Process pēc p. 1. kas atšķiras ar to, ka etapā (3) iegūto 3(7?)-aril-4-aminosviestskābes esteri (2R) pārvērš R-enantiomērajā 3-aril-4-aminosviestskābē (17?) ar skābās hidrolizēs
5 paņēmienu.
31. Process pēc p. 1., kas atšķiras ar to, ka etapā (3) iegūto 4(S)-aril-2-piroIidinonu (3S) pārvērš S-enantiomērajā 3-aril-4-aminosviestskābē (15) ar skābās hidrolizēs paņēmienu.
LVP-06-28A 2006-02-23 2006-02-23 Enzymatic resolution of racemic 3-aryl-4-aminobutyric acids LV13635B (en)

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LVP-06-28A LV13635B (en) 2006-02-23 2006-02-23 Enzymatic resolution of racemic 3-aryl-4-aminobutyric acids
PCT/EP2007/051538 WO2007096314A2 (en) 2006-02-23 2007-02-18 Enzymatic resolution of racemic 3-aryl-4-aminobutyric acid
EA200801878A EA014980B1 (ru) 2006-02-23 2007-02-18 Энзиматический метод разделения рацемической 3-арил-4-аминомасляной кислоты

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Publication number Priority date Publication date Assignee Title
WO2015087291A1 (en) 2013-12-13 2015-06-18 Jsc Olainfarm 3-carboxy-4-(r)-phenylpyrrolydine-2-one salt and its use

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JP5380743B2 (ja) * 2008-06-19 2014-01-08 住友化学株式会社 光学活性な４−アミノ−３−置換フェニルブタン酸の製造方法
FR3054218B1 (fr) * 2016-07-22 2020-03-06 Universite De Rouen Procede de dedoublement de sels de baclofene
CN115282928B (zh) * 2022-08-04 2023-08-15 杭州佳嘉乐生物技术有限公司 一种新型分离介质及其应用

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US6051734A (en) * 1995-12-20 2000-04-18 Farmarc Nederland B.V. Process for the optical resolution of 3-(p-chlorophenyl)-glutaramide
US5843765A (en) * 1997-01-31 1998-12-01 National Research Council Of Canada Streptomyces microorganism useful for the preparation of (R)-baclofen from the racemic mixture

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015087291A1 (en) 2013-12-13 2015-06-18 Jsc Olainfarm 3-carboxy-4-(r)-phenylpyrrolydine-2-one salt and its use

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WO2007096314A3 (en) 2007-11-01
EA200801878A1 (ru) 2009-04-28
WO2007096314A2 (en) 2007-08-30

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