AU668692B2 - Chiral glutarate esters, their resolution and derived glutarimide compounds - Google Patents
Chiral glutarate esters, their resolution and derived glutarimide compounds Download PDFInfo
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- AU668692B2 AU668692B2 AU24774/92A AU2477492A AU668692B2 AU 668692 B2 AU668692 B2 AU 668692B2 AU 24774/92 A AU24774/92 A AU 24774/92A AU 2477492 A AU2477492 A AU 2477492A AU 668692 B2 AU668692 B2 AU 668692B2
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- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
- C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
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- 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
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
- C12P7/44—Polycarboxylic acids
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Description
OPI DATE 16/03/93 AOJP DATE 27/05/93 APPLN. ID 24774/92 PCT NUMBER PCT/GB92/01541 AU9224 774 INTERNATIONAL APPLICATION PUB3LIS H ED UNDEIR 1khzt FA Iz' tNIkUUrr-KA L1UN I mctt I I k.pCT) (51) International Patent Classification 5 (11) International Publication Number: WNO 93/04058 C07D 401/04, 2 13/55, 211/88 Al (3 nentoa ulcto ae ac 93(40.3 C12P 41100, 17/12, 17/16 (3 nentoa ulcto ae ac 93(40-3 C12N 1/15 C12N 1/15 (21) International Application Number: PCT/GB92/01541 (74) Agent: GILL JENNINGS EVERY; 53/64 Chancery Lane, London WC2A IRFN (GB).
(22) International Filing Date: 21 August 1992 (2 1.08.92) (81) Designated States: AU, CA, JP, US, European patent (AT, Priority data: BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, 9118149.5 22 August 1991 (22.08.9 1) GB NL, SE).
9118151.1 22 August 1991 (22.08.91) GB C4'/~Q~e /VC '~/LTDPublished (71) Applicant (for all designated States except US):-G1-H4- With international search report.
*.M4FE.B-[GB/GB]; Science Park, Milton Road, Cambridge CB34 4WE (GB).
(72) Inventors; and ~:ztk Inventors/Applicants (for US only) :EVANS, Christopher, .4 Thomas [GB/GB]; Stable Cottage, Fowlmere Road, Heydon, Hertfordshire SG8 8PU McCAGUE,- Raymond [GB/GB; 5 Mansfield Close, Milton, Cambridge CB4 6EE TAYLOR, Stephen, John, Clifford [GB/GB]; 52 Cambridge Road, Ely, Cambridgeshire CB7 4MT L eNT (54) Title: CHIRAL GLUTARATE ESTERS, THEIR RESOLUTION AND DERIVED GLUTARIMIDE COMPOUNDS (57) Abstract Enantiomers of chiral com -pounds such as 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione (Rogletimide) are prepared by cyclising the corresponding diesters such as diethyl 2-ethyl-2-(4-pyridyl)glutarate which themselves are prepared by enantiospecific biotransformation of the racemic diester.
1 Field of the Invention This invention relates to chiral compounds and their resolution.
Background of the Invention The racemate of 3-ethyl-3-(4-pyridyl) piperidine- 2,6-dione (Rogletimide), also known as pyridoglutethimide (described herein as 4-PG), has been demonstrated to be effective for the treatment of hormone-dependent breast cancer. As described by Foster et al, J. Med. Chem. 28: 200-204 (1985), the mode of action of 4-PG is thought to be inhibition of the enzyme aromatase and therefore of oestrogen biosynthesis. Derivatives of 4-PG, including alkyl derivatives, may be as good or better aromatase inhibitors; see McCague and Rowlands, J. Med. Chem., in press.
As described by McCague et al, J. Chem. Soc. Perkin Trans. 1: 196-198 (1989), the (R)-enantiomer of 4-PG has been measured to be twenty times as potent an inhibitor of aromatase as the (S)-enantiomer. It is therefore likely that the (R)-isomer is essentially the active component in the racemate.
The separate enantiomers of 4-PG have been prepared, using a camphor-derived chiral auxiliary. This agent is expensive, and makes the method impractical for production of more than gram quantities of product.
Summary of the Invention The present invention provides the meth.;,! for 30 preparing, in the form of at least predominantly one enantiomer thereof, a chiral aromatase inhibitor compound Sof formula I Z
X
I ~II~~ 1/1 wherein X is CI_ 10 alkyl, Z is H or 5-alkyl and Y is a cyclic group, which comprises; contacting a racemic compound of formula II x
Z
ROOC COOR'
II
wherein R and R' are the same or different esterifying radicals with an enatiospecific esterase, and cyclising the compound of formula II by amidation.
According to the present invention, the problem of producing enantiomers of 4-PG and its analogues is solved by their preparation from precursors, in enantiomeric form, that can be resolved much more easily. The novel method, that is practical for the bulk production of a single enantiomer of 4-PG, is based on the microbial or enzymic biotransformation of an ester precursor.
The enantiomeric products of the invention are of formula I, and the novel precursors are of formula II, 25 these formulae being defined in claim 1. Racemic formula I c i I" WO 93/04058 PCT/GB92/01541 2 II compound may be contacted with an enantiospecific esterase that enriches the mixture in terms of one enantiomer, by reacting with the other enantiomer to form the corresponding acid (which may be separated); partial enrichment may be enhanced by further resolution with a conventional camphor-derived chiral auxiliary.
Biotransformation can be conducted using a known esterase.
Description of the Invention 4-PG is the compound of formula I when X is ethyl, Y is 4-pyridyl and Z is hydrogen. For the purposes of illustration only, the process involved in the invention will now be described with reference to the production of enantiomeric 4-PG, as outlined in the Chart. The Chart also shows how compounds of formula II (specifically formula 2) may be prepared by sequential alkylation of an alkyl 4-pyridylacetate with iodoethane, e.g. in the presence of potassium t-butoxide and t-butyl alcohol and then with an alkyl acrylate.
R and R' are esterifying groups, suitably alkyl residues containing up to 10 carbon atoms consisting of straight-chain alkyl, branched alkyl, arylalkyl, and aryl optionally substituted with, for example, halogen. For the purpose of the invention, the simplest alkyl groups (R,R' methyl or ethyl) are adequate, and in terms of simplifying the chemical processing, are preferred.
The subsequent step shown in the Chart, is characteristic of the invention. It is based on the discovery of biocatalysts that preferentially hydrolyse one enantiomer of a racemic diester to give opticallyenriched residual diester and the monoester There are biocatalysts that produce the R-enantiomer of the ester-acid biocatalysts A in the Chart) and those that produce the S-enantiomer (biocatalysts B).
Suitable esterase activities may be available from acylase I (Aspergillus), esterase 30,000, Rhizopus Japonicus lipase, F3 lipase, A2 lipase (porcine pancreas), r i' I I L Irr -rr 3 F6 lipase (from Candida), pig liver esterase, CE lipase and AY lipase. Cholesterol esterase is an alternative.
One example of a biocatalyst suitable for the biotransformation is the microbial strain P3U1 which can produce R-ester acid of greater than 60% ee. Another suitable biocatalyst (of type B) is Trichosporon ENZA 1-3, whose characteristics, including its enantiospecificity for the conversion of aralkanoic acid esters into the acid, e.g. Ketoprofen, are described in publication W093/04189.
Strain ENZA I-3 has been deposited under the terms of the Budapest Treaty, on 20th August 1991, with the International Mycological Institute, Kew, UK; the accession number is 348917. Strain P3U1 has also been deposited, under the terms of the Budapest Treaty, on 20th August 1992, at NCIMB; the accession number is 40517.
Conversion of the biotransformation products, which are readily separated by solvent extraction at neutral pH, into enantiomerically-enrichea 4-PG is by conventional chemical techniques. Thus, diesters can be converted into by heating with methanolic ammonia under pressure, and ester-acid can be converted into by heating with urea.
A further feature of the invention is the discovery of a process for producing essentially optically pure from ptically-enriched material derived from the biotransformation. It is therefore not essential that the S' biotransformation is absolutely specific for 30 enantiomerically pure to be manufactured. In an e embodiment of this aspect of the invention, the opticallyenriched is converted (in the case of (R)-enantiomer) to the (1R)-(-)-10-camphorsulphonate salt and the salt recrystallised, for example from ethyl acetate:ethanol (10:1) whereupon material that has 0 to 50% ee in favour of (R or S)-glutarimide crystallises and leaves almost optically pure salt in solution. Release of from I I C_ ill WO 93/04058 PCT/GB92/01541 4 its salt and subsequent recrystallisation of the almost optically pure can raise it to optical purity.
The following Examples illustrate the invention.
Example 1 Growth of P3U1 The strain P3U1 was streaked onto nutrient agar plates and 5 g/l glucose, and incubated at 23 0 C for 60 hours.
Seed flasks, containing 150 ml growth medium (1 g/l
(NH
4 2 SO4; 2 g/l KH 2
PO
4 0.25 g/l MgS04; 0.1 g/l CaCl 2 0.1 ml TES; 10 ml YE) per 500 ml flask, were inoculated from the nutrient agar plates and shaken at 23 0 C, 350 rpm for 24 hours. After 24 hours the optical density at 520 nm had reached 2.1. This was used to inoculate production fermenters (using a 10% inoculum): 1.5 1 growth medium per Anglicon fermenter. These were grown at 23 0 C with agitation; aeration was adjusted to keep the DOT above After 24 hours, the optical density at 520 nm had reached The cells were then harvested at 5000 rpm for min.
Example 2 Biotransformation The cell mass of P3U1 cells, harvested by centrifugation, was resuspended to an optical density of 2 (520 nm).in 10 mM KH 2
PO
4 pH 7, containing yeast extract (+)-Dimethyl 2-ethyl-2-(4-pyridyl)glutarate was added to a final concentration of 3 g/l. The cells were stirred at 23 0 C without aeration or pH control. The enantiomeric excess (ee) of the substrate was monitored as the hydrolysis progressed (extraction of the diester into cyclohexane, followed by HPLC analysis of the cyclohexane I layer on a Chiracel-OJ-column). After 72 hours, the ee of the remaining diester was 66%, and the biotransformation was harvested. Cells were removed by centrifugation, then diester extracted with ethyl acetate (3 x 1 The aqueous layer was then salted (10% weight NaCl) and the pH adjusted to 2.6 usirj conc. HCl. The product was then extracted with tetrahydrofuran (THF). The THF extracts were combined and evaporated under reduced pressure to give a brown oil, which was dried by azeotroping with toluene.
WO 93/04058 PCT/GB92/01541 The toluene solution was mixed with an equal volume of acetone, and the resulting precipitate of inorganic salts filtered off. The solvents were evaporated to give a brown oil which solidified on standing (yield 4.1 This was substantially E-2-ethyl-2-(4-pyridyl)glutaric acid 1monomethyl ester.
Example 3 Cyclisation Cyclisation to the imide was effected by heating the product from Example 2 with an equal weight of urea for min.
The product was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was dried (MgSO 4 and then evaporated to give crude 3ethyl-3-(4-pyridyl) pyri44ie-2,6-dione (1.1 g) This was purified by flash chromatraphy on silica (eluting with 2:1 ether:triethylamine) to give pure enantiomerically enriched product (300 mg). The ee was found to be 56% as determined by HPLC on a Daicel Chiracel OJ column.
Example 4 ee Enrichment The purified imide from Example 3 (300 mg) was dissolved in ethyl acetate (10 ml). To this solution was added 1R-(-)-camphorsulphonic acid (1.1 mol equivalent, 352 mg). After 0.5 hr stirring at ambient temperature the mixture was brought to reflux and sufficient ethanol (3 ml) added to dissolve the solid. The clear solution was allowed to cool slowly to 50C after which the solid was removed by filtration (190 mg of racemic material). The I enantiomeric excess of the product in the liquors was found i to be 96.2%. The solvent was removed and the above recrystallisation process repeated. The final liquors l contained R-3-ethyl-3-(4-pyridyl)piperidine-2, 6-dione as its R-camphorsulphonate salt in 97.3% enantiomeric excess.
The R-enriched R-camphorsulphonate salt solution was concentrated to dryness then suspended in water (5 ml).
The mixture was basified to pH 9 with 2 N sodium hydroxide solution. The product was extracted into ethyl acetate and the organic extracts dried (MgSO 4 The final product was :1 I 'CC~ WO 93/04058 PCT/GB92/01541 6 isolated and purified by flash chromatography as described in Example 3.
Example 5 Biotransformation Biotransformation on the same substrate as Example 2 was carried out in a baffled conical flask (500 ml) containing 0.1 M KH2PO 4 (100 ml) adjusted to pH 7, cyclohexane (100 ml), dimethyl ester (1 g) and Mucor javanicus lipase (700 mg). The flask contents were shaken at 23°C, and the ee of the remaining substrate in the cyclohexane layer monitored by HPLC. After 48 hours, the ee of the remaining substrate was 46% (enriched in the pro- R diester), at a conversion of 84%.
Example 6 Biotransformation The procedure described in Example 5 was carried out but using Candida cylindracea lipase as the biocatalyst.
After 48 hr, the ee of the remaining diester was 66% in favour of S-enantiomer, at a conversion of 72%.
Example 7 Biotransformation ENZA 13 was inoculated from a freshly-grown YM (Difco) agar plate into 5 ml growth medium in a 20 ml container (the growth medium comprised 1 g/l (NH 4 2 S0 4 2 g/l KH 2
PO
4 0.25 g/l MgSO 4 .7H 2 0, 0.1 g/l CaCl 2 .2H 2 0, 0.1 ml/l trace element solution, 10 g/l yeast extract, adjusted to pH with sodium hydroxide). This was incubated at 23 0 C for 24 hours with shaking. The cells were then spun and resuspended in 5 ml reaction buffer in a 20 ml container (the reaction buffer comprised 10 mM sodium phosphate, g/l yeast extract (Fould Springer), 50 p1/1 Tween 80, 3 g/l (+)-dimethyl 2-ethyl-2-(4-pyridylglutarate). This was shaken for 41 hours. The enantiomeric excess (ee) was measured by extraction of the diester into cyclohexane followed by HPLC analysis of the cyclohexane layer on a Chiracel-OJ column. After 22 hours, the residual diester had an ee of 54% in favour of the R configuration.
WO 93/04058 WO 9304058PCT/GB92/01541 co 2
R
CO 2 R' CO 2
R
racemate (2) biocatalyst
A
biocata] yst
B
C0 2 R' C0 2
R
(3a) Et c2 cC0 2
R
(4b) (R )-enantiorner Et CO 2 R' CO 2
R
(3b) (R)-enantlomer co2 co 2
R
(4 a) (S )-enantiomer (S )-enant.Iomer
H
R-enantiomer S-enantiomer
Claims (13)
1. The method for preparing, in the form of at least predominantly one enantiomer thereof, a chiral aromatase inhibitor compound of formula I wherein X is C1 10 alkyl, Z is H or 5-alkyl and Y is a cyclic group, which comprises; contacting a racemic compound of formula II Z X ROOC COOR' C C *l Sfc wherein R and R' are the same or different esterifying radicals with an enatiospecific esterase, and cyclising the compour of formula II by amidaticn.
2. A method according to claim 1, wherein R and R' are each a Cl_ 10 alkyl group.
3. A method according to cla.im 2; wherein X is ethyl. c I Ir
4. A method according to any preceding claim, wherein Y is 4-pyridyl. A method according to any preceding claim, wherein Z is H.
6. A method according to claim 1, wherein the compound of formula I is (R)-4-pyridoglutethimide.
7. A method according to any preceding claim, wherein R and R' are each methyl or ethyl.
8. A method according to any preceding claim, wherein cyclisation comprises reaction with urea or ammonia.
9. A method according to any one of the preceding claims, wherein following contacting the racemic compound of formula II with an enantiospecific esterase, a further resolution step is optionally performed, and then the compound of formula II is separated from the acid formed by the esterase reaction. A method according to claim 9, wherein the esterase has the characteristics of Trichosporon ENZA 1-3, IMI 348317 or of P3U1, NCIMB 40517.
11. A method according to claim 9 or claim 10, wherein further resolution is conducted, using a camphorsulphonate salt or other resolution agent.
12. A compound of formula II as defined in any of claims 1 to 7 wherein X is C 1 10 alkyl, Z is H or and Y is ayl- group, in the form of one enantiomer substantially free of the other enantiomer.
13. A compound according to claim 12, wherein X is ethyl j and Y is 4-pyridyl.
14. A compound according to claim 12 or claim 13, wherin the one emantiomer is the (R)-enantiomer. DATED this 17th day of November 1995 CHIROSCIENCE LIMITED Patent Attorneys for the Applicant F.B RICE CO e- i. L- I~ h Y' r *i i 13. A compound according to claim 12, wherein X is ethyl and Y is 4-pyridyl. 14. A compound according to claim 12 or claim 13, wherin the one emantiomer is the (R).-enantiomer. DATED this 17th day of November 1995 CHIROSCIENCE LIMITED Patent Attorneys for the Applicant F.B RICE CO -1 I Applicant's or agent's file Itrainlapiain1 reference°number /3851/03 lt e 'GB 2 2 0 1 5 4 1 INDICATIONS RELATING TO A DEPOSITED MICROORGANISM (PCT Rule 13bis) A. The indications made below relate to the microorganism referred to in the description on page 3 ,line 12-15 B. IDENTIFICATION OF DEPOSIT Further deposits are identified on an additional sheet Name of depositary institution International Mycological Institute Address of depositary institution (including postal code and counlry) Ferry Lane Kew Surrey TW9 3AF United Kingdom Date of deposit Accession Number August 1991 348917 C. ADDITIONAL INDICATIONS (leave blank if not applicable) This information is continued on an additional sheet E The deposited microorganism is available only to an expert, e.g. in accordance with the provisions of Rule 28 EPC. D. DISIGNATED STATES FOR WHICH INDICATIONS ARE MADE (if the indicatlion are notfor all designated Slates) E. SEPARATE FURNISHING OF INDICATIONS (leave blank if not applicable) The indications listed below will be submitted to the International Bureau later (specify the generalnature oftheindications 'Accession Number of Deposit') For receiving Office use only For International Bureau use only This sheet was received with the international application This sheet was received by the International Bureau on: Authorized officer Authorized offer p. J. SUIPTOli ROOM G.Y73 EXT, 442Z Form PCr/RO/134 (July 2992) Applicant's or agent's file International application' referenice number '/u/3851/ 032 n1s 1 INDICATIONS RELATING TO A DEPOSITED MICROORGANISM (PCT Rule 13bis) A. The indications made below relate to the microorganism referred to in tbe description on page 3 ,line 15-17 B. IDENTIFICATCION OF DEPOSIT Further deposits are identified on an additional sheet Name of depositary institution NCIMB Ltd. Address of det.ositary institution (including postal code and country) 23 St. Machar Drive Aberdeen AB2 iRY United Kingdom Dateof epost Acession Number Dtofdpst 20th August 1992 40517 C. ADDITIONAL- INDICATIONS (leave blank if noapplicabl) This information is continued on an additional sheet The deposited microorganism is available only to an exper, e.g. in accordance with the provisions of Rule 28 EPC. D. DESIGNATED STrATES FOR WHICH INDICATIONS ARE MADE (if teinicatiosarent for all designaed States) E. SEPARATE FUTRNISHING OF INDICATIONS (leave blank if not applicable) The indications listed below will be submitted to the International Bureau later (specify the general nature ofth inications 'Accession Number of Deposit~) For receiving Office use only 7' This sheet was received with the international application Authorized officer P. J. SHIPTOhI LROOM G.Y73 EXTf. 4427. Form PCT/RO/134 (July 1992) For International Bureau use only jJThis sheet was received by the International Bureau on: Authorized officcr I INTERNATIONAL SEARCH REPORT International Appikcation No PCT/GB 92/01541 I. CLASSIFICATION OF SUBJECT MATTER (if sevesral classification symbols apply, indicate 2aU)6 According to International Patent Classification (1PC) or to both National C3assifiCatioE And IPC Int.Cl. 5 C070401/04; C070213/55; C07D211/88; C12P41/OO C12P17/12; C12P17/16; C12Nl/15; IIC12N1/15 11. FIELDS SEARCHED Minimum Documentation Searched7 Classification Syiten Classification Symbols Int.Cl. 5 C12P ;C07D C12N Documentation Searched other than Minimum Documentation to the. Extent that such Documents are included in the Fields Searchedl MI. DOCUMENTS CONSIDERED TO BE RELEVANT 9 Category 0 Citation of Dcoment, IL with indication, whom appropriate, of the relevant pasazges 1 2 Relevant to Claim No.13 X EP,A,O 258 617 (ASTA) 1-5,8,9 9 March 1988 see page 2, line 36 line 42; claims X TETRAHEDRON, (INCL. TETRAHEDRON REPORTS) 18 vol 45, no. 18, 1989, OXFORD GB pages 6011 6016 AILEEN M.BOSS ET AL. 'A concise synthesis of racemic pyridoglutethimide and its resolution using chiral stationary phase HPLCI see the whole document oS pecial categorn of cited documents 10 IT' later document published after the international filing data document defining the general state of the art which isntcted to undestand the principle or theory uneligthe considered. to be of patcua Isevc Inoreprioiydtn n o ncnfitwt h u earlier document but published on or after the international -XI document of particular relevance; the claimed invention filing date a2-nnot be considered novel or cannot be considered to 'U document which may throw doubts on priority claim(s) or invwive an inventive step which is cited to establish the publication date of another -r document of particula relevance; the claimed Invention citation or other Special reason (as specified) cannot be considered to involve an inventive step when the 0' document referring to an oral disclosure use, exhibition or document is combined with one or more other such docu- other meanus ments, such combination Mung obvious to a person skilled "P document pubised prior to the international fling date but In the amt latw than te priority date claimed W document member of C, rs same patent family IV. CRTIFICATION1 Date of the Actual, Completion of the Internationa Search Date of Mailing of this international Search Report NOVEMBER 1992 .0 3 International Searching Authority Signature of Authorized Officer EUROPEAN PATENT OFFICE DELANGHE L.L.M. Forst PCIVISJ4IO (oA~ theeti Jm t9U POT/GB 92/01541 Interninal Application No MI. DOCUMENTS CONSIDERED TO BE RELEVANT (CONTINUED FROM THE SECOND SHEET) Caegr CiJtation of Document, with Indication, where appropilte, of the relevant passges Relevant to Claim No. JOURNAL OF THE CHEMICAL SOCIETY. 1989, LETCHWORTH GB pages 196 198 RAYMOND MCCAGUE ET AL. 'Synthesis of the aroniatase inhibitor 3-ethyl-3-(4-pyridyl )piperidine-2,6-dione and its enantiomers.' cited in the application see the whole document DE,C,3 224 019 (TAKARA SHUZO) 16 February 1984 see page 1, column 1 column 2 AGRICULTURAL AND BIOLOGICAL CHEMISTRY. vol. 51, no. 7, July 1987, TOKYO JP pages 1833 1838 G.M. RAMOS TOMBO ET AL 'Application of microbes and microbial esterase to the preparation of optically active N-acetylindoiine-2-carboxylic acid' see the whole document 18 1,10 1,10 6 1~ CTIISJI (extra~g A" j-y 106$ ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION No. GB SA 9201541 63638 This annex lists dhe patent family members relating to the patent docuaments cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on The European Patent Office is in no way liable for these particulars which are nmrey given for the purpose of information- 2 5/ 11/92 Patent document Publication Patent family Publication cited in search report date mcmher(s) date j EP-A-0258617 09-03-88 IJE-A- OE-A- J P-A- US-A- ZA-A- 3724520 3777500 63041458 4839370 8705653 03-03-88
23-04-92 22-02-88 13-06-89 15-02-88 DE-C-3224019 16-02-84 None U 0 a. 0 For more details mbo~it thia ~nex ~e Offidal Jo~anal of the Eurupean Patant Offlee, No. 12/HZ
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9118151 | 1991-08-22 | ||
| GB919118151A GB9118151D0 (en) | 1991-08-22 | 1991-08-22 | Chiral compounds and their resolution |
| GB919118149A GB9118149D0 (en) | 1991-08-22 | 1991-08-22 | Araylalkanoic acid resolution |
| GB9118149 | 1991-08-22 | ||
| PCT/GB1992/001541 WO1993004058A1 (en) | 1991-08-22 | 1992-08-21 | Chiral glutarate esters, their resolution and derived glutarimide compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2477492A AU2477492A (en) | 1993-03-16 |
| AU668692B2 true AU668692B2 (en) | 1996-05-16 |
Family
ID=26299439
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU24774/92A Ceased AU668692B2 (en) | 1991-08-22 | 1992-08-21 | Chiral glutarate esters, their resolution and derived glutarimide compounds |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0599959A1 (en) |
| JP (1) | JPH06510284A (en) |
| AU (1) | AU668692B2 (en) |
| CA (1) | CA2116108A1 (en) |
| WO (1) | WO1993004058A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9410721D0 (en) * | 1994-05-27 | 1994-07-13 | Chiroscience Ltd | Chiral compounds and their resolution |
| AR022725A1 (en) * | 1999-02-26 | 2002-09-04 | Schering Corp | ENZYMATIC HYDROLYSIS ENANTIOSELECTIVA OF ESTERES 3-SUBSTITUTES OF GLUTARIC ACID |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0258617A1 (en) * | 1986-07-31 | 1988-03-09 | MADAUS Aktiengesellschaft | 3,3-Disubstituted-piperidine-2,6-dione derivatives |
| AU1417592A (en) * | 1991-03-22 | 1992-10-21 | British Technology Group Limited | Heterocyclic compounds, their preparation and pharmaceutical use |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3224019C1 (en) * | 1982-06-28 | 1984-02-16 | Takara Shuzo Co., Ltd., Kyoto | Process for the preparation of alkyl beta -(S)-aminoglutarates |
-
1992
- 1992-08-21 CA CA002116108A patent/CA2116108A1/en not_active Abandoned
- 1992-08-21 EP EP92918126A patent/EP0599959A1/en not_active Withdrawn
- 1992-08-21 AU AU24774/92A patent/AU668692B2/en not_active Ceased
- 1992-08-21 JP JP5504204A patent/JPH06510284A/en active Pending
- 1992-08-21 WO PCT/GB1992/001541 patent/WO1993004058A1/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0258617A1 (en) * | 1986-07-31 | 1988-03-09 | MADAUS Aktiengesellschaft | 3,3-Disubstituted-piperidine-2,6-dione derivatives |
| AU1417592A (en) * | 1991-03-22 | 1992-10-21 | British Technology Group Limited | Heterocyclic compounds, their preparation and pharmaceutical use |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1993004058A1 (en) | 1993-03-04 |
| CA2116108A1 (en) | 1993-03-04 |
| JPH06510284A (en) | 1994-11-17 |
| EP0599959A1 (en) | 1994-06-08 |
| AU2477492A (en) | 1993-03-16 |
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