AU2572495A - Chiral compounds and their resolution - Google Patents
Chiral compounds and their resolutionInfo
- Publication number
- AU2572495A AU2572495A AU25724/95A AU2572495A AU2572495A AU 2572495 A AU2572495 A AU 2572495A AU 25724/95 A AU25724/95 A AU 25724/95A AU 2572495 A AU2572495 A AU 2572495A AU 2572495 A AU2572495 A AU 2572495A
- Authority
- AU
- Australia
- Prior art keywords
- compound
- formula
- enantiomer
- nitrophenyl
- ethyl
- 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.)
- Abandoned
Links
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
-
- 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
- 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
Description
CHIRAL COMPOUNDS AND THEIR RESOLUTION
Field of the Invention
This invention relates to chiral compounds that are useful as intermediates in the synthesis of pharmaceutically-active glutarimides, and to their resolution.
Background of Invention
Racemates of 3,3-disubstituted glutarimides such as 3- ethyl-3-(4-aminophenyl)piperidine-2,6-dione (aminoglutethimide) and 3-ethyl-3-(4-pyridyl)piperidine- 2,6-dione (rogletimide) have been shown to be effective for the treatment of hormone-dependent breast cancer; see Smith et al, Lancet ii:646 (1978), and Foster et al , J.Med. Chem. 28:200 (1985). The mode of action of these compounds is considered to be inhibition of the enzyme aromatase that catalyses the formation of estrogens from androgens; thus the compounds inhibit tumours whose growth is promoted by estrogens.
McCague et al , J.Med.Chem. 35:3699-3704 (1992), disclose that derivatives of rogletimide, including 5-alkyl derivatives, may have improved aromatase inhibition activity. Aromatase inhibition by the enantiomers of aminoglutethimide, rogletimide and also cyclohexylaminoglutethimide, in vitro , is reported by Ogbunude et al , Chirality .6:623-626 (1994).
Graves et al , Endocrinology 105:52 (1979), disclose that the (R)-enantiomers of these compounds are much more potent as inhibitors of aromatase than the (S)-enantiomers. Therefore, it is likely that the (R)-enantiomers are essentially the active components in the racemates, and so a process for their preparation is desirable.
The separate enantiomers of aminoglutethimide and rogletimide have been prepared respectively by repeated recrystallisation of tartrate salts, and by using camphor- derived chiral auxiliaries; see Finch et al , Experientia 31:1002 (1975), and McCague et al , J.Chem.Soc.Perkin Trans. 1:196-8 (1989). Separation has also been accomplished by
chromatography on chiral stationary phases based on tartramides or triacylcelluloses. However, these methods are not amenable to economic large-scale working appropriate for the manufacture of the bulk single- enantiomer drug substance.
WO-A-9304058 discloses a process for the manufacture of such glutarimide compounds, by way of biocatalytic resolution of glutarate diesterε. Only the less hindered ester function is hydrolysed by an appropriate biocatalyst, with a degree of enantiospecificity showing that the biocatalyst can distinguish aryl, ethyl and carboxylic ester substituents borne on a quarternary carbon atom. While only moderate specificity was observed in the case of precursors of rogletimide, the biotransformation products were easily converted into rogletimide and means to then increase the enantiomeric excess was found.
Summary of the Invention
Whereas in WO-A-9304058 the substrate for biotransformation is a diester, it has now been found that a corresponding ester-nitrile (see formula II in claim 1, but R is not H) is a satisfactory substrate. The desired enantiomer can be separated from the unwanted enantiomer, and readily cyclised, e.g. using acid, to form the same product (I) as in WO-A-9304058.
According to one aspect of the present invention, effective biocatalytic resolution, using available esterases, is possible using ester-nitriles of formula II.
Good enantiospecificities have been obtained for resolution by way of biocatalytic hydrolysis of the ester function. Thus the appropriate enzyme is able to distinguish between substituents, e.g. aryl, ethyl and nitrile, borne on a quarternary carbon atom. More particularly, racemic formula 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 (II: R = H) which may be separated; partial enrichment may be enhanced by
further resolution with a tartaric acid or conventional camphor-derived chiral auxiliary.
Description of the Invention
As a substrate for biotransformation, in formula II, R is an esterifying group, suitably an alkyl residue containing up to 10 carbon atoms, e.g. straight-chain alkyl, branched alkyl, arylalkyl and aryl optionally substituted with, for example, halogen. For the purpose of the invention, the simplest alkyl group (R = methyl or ethyl) is adequate, and in terms of simplifying the chemical processing, is preferred. For cyclisation, after biotransformation, R may be H; alternatively, depending on the enantiomer that is desired, R may be unchanged.
X and Z are each H or an organic group. X may be, for example, C1-10 alkyl such as ethyl. Z is preferably H or a C1-10 alkyl group, e.g. to give a 5-alkyl product. The compound of formula I may be any aromatase inhibitor such as aminoglutethimide (I: X = ethyl, Y = 4-aminophenyl, Z = H) or any analogue, e.g. the specific compounds described above, or isopropylglutethimide. The compound of formula I may also be an intermediate for hypotensive agents such as verapamil. Y is thus defined; in general, Y (or Ar in the Chart) is a cyclic group, either an aryl, carbocyclic or heterocyclic radical, e.g. of up to 12 C atoms, including any substituents. Y is preferably dimethoxyphenyl, 4-pyridyl, 4-aminophenyl (optionally N- protected), isopropyl-phenyl or cyclohexylphenyl. Especially as a precursor to Y=aminophenyl, e.g. by catalytic hydrogenation, Y may also be nitrophenyl; (R) -3- ethyl-3-(4-nitrophenyl)piperidine-3,6-dione is a novel compound. Compounds of formula II in which Y is nitrophenyl give especially good biotransformation yields.
For the purpose of illustration only, the process involved in the invention may be described with reference to the production of, say, enantiomeric aminoglutethimide, as outlined in the Chart. Compounds of formula II (specifically formula 1) may be prepared by methods known
to those skilled in the art, and exemplified below. One such method involves Michael addition to an acrylate ester (see Example 4).
The first step shown in the Chart is a characteristic of the invention. It is based on the use of biocatalysts that preferentially hydrolyse one enantiomer of a racemic nitrile (1) to give optically-enriched residual ester (2) and the acid (3 ) . There are biocatalysts that produce the R-enantiomer of the ester (i.e. 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), F6 lipase (from Candida) , pig liver esterase, CE lipase and
AY lipase. Cholesterol esterase is an alternative.
Examples of biocatalysts A are Candida cylindracae lipase and enzyme activities of the genera in Examples 8 to 10.
Another example of a biocatalyst suitable for the biotransformation is the microbial strain P3U1, NCIMB 40517, which can produce R-ester acid of greater than 60% ee. Another suitable biocatalyst (of type B) is Trichosporon ENZA 1-3, IMI 348917, whose characteristics, including its enantiospecificity for the conversion of aralkanoic acid esters into the acid, e.g. (S)-ketoprofen, are described in WO-A-9304189. α-Chymotrypsin is another suitable biocatalyst of category B.
A further biocatalyst is obtainable from any fungus of the type described in WO-A-9420634 for the enantiospecific hydrolysis of arylpropionic acid esters. A specific fungus of this type is Ophiostoma novo-ulmi , IMI 356050.
In specific examples of the biotransformation, the phenylglutaronitrile ester (Ar = Ph, R = Me) with Candida antarctica lipase gave hydrolysis of the ester function to the acid with an enantiospecificity (E) = 12. The nitrophenyl compound (Ar = 4-nitrophenyl, R = Me) with α- chymotrypsin gave a transformation with E = 39. The same
substrate with esterase derived from the given fungus Ophiostoma novo-ulmi also gave transformation with the opposite specificity.
Conversion of the biotransformation products, which are readily separated by solvent extraction at neutral pH, into enantiomerically-enriched glutarimide is by conventional chemical techniques.
Conversion of such nitrile esters to the glutarimides was accomplished easily under such conditions as heating with acid, e.g. a mixture of acetic acid and sulphuric acid, to provide the optically-active glutarimide compounds. These conditions are known in the conversion of racemic nitrile-esters into the racemic glutarimides, aminoglutethimide and rogletimide.
The following Examples 1 and 4 illustrate the preparation of nitrile-esters (II) that are substrates for biotransformation, and Example 6 illustrates a relevant reduction. Examples 2, 5 and 8 to 10 illustrate biotransformations, and Examples 3 and 7 illustrate cyclisation reactions, in accordance with the invention. Examples 1 to 3, and Examples 4 to 7, provide different routes to the same product.
Example 1 Methyl 4-cyano-4-(4-aminophenyl)hexanoate
A 3-necked round-bottomed flask was charged with methyl 4-cyano-4-(4-nitrophenyl)hexanoate (20.0 g), 90% ethanol (1000 ml) and PtO2 (1.0 g). The vessel was then evacuated and charged with nitrogen. The mixture was stirred vigorously and subjected to H2 at atmospheric pressure supplied via a balloon. The catalyst was removed by filtration through celite and the solvent removed under reduced pressure to give methyl 4-cyano-4-(4-aminophenyl)- hexanoate (18 g, 100%) as a viscous, brown oil.
Example 2
A 500 ml jacketed biotransformation vessel was charged with 0.1M KH2PO4, pH 7.0 (250 ml) and methyl 4-(4- aminophenyl)4-cyanohexanoate (5.0 g, 20.3 mmol). Candida cylindracea lipase (CCL; 5.0 g) was introduced and the
mixture was agitated using an overhead stirrer. Temperature was maintained at 30°C with the aid of a thermocirculator and the pH controlled by a probe linked to an autotitrator. The biotransformation was allowed to proceed until 10 ml of IM NaOH had been added (equivalent to 50% conversion). This took about 3 hours. At this point, the biotransformation was quenched by the addition of NaCl (25 g) and the resulting mixture was extracted with diethyl ether (250 ml x 4) . The pH of the aqueous solution was then adjusted to 3 using cone. HCl and the mixture extracted with ethyl acetate (400 ml x 3). The extracts were pooled, dried and concentrated under reduced pressure, yielding 1.8 g (38%) of 4-(4-aminophenyl)-4-cyanohexanoic acid, enriched in the (R)-enantiomer, in the form of a brown oil. Without further treatment, a sample of this material was reacted as described in Example 3.
Example 3 (R)-Aminoglutethimide
4-(4-Aminophenyl)-4-cyanohexanoic acid (Example 2; 1.8 g, 7.7 mmol), enriched in the {R)-enantiomer, was dissolved in glacial acetic acid (6.0 ml) contained in a 25 ml round-bottomed flask. The resulting mixture was heated to 60°C with the aid of an oil bath followed by dropwise addition of cone. H2SO4 (3.0 ml). The solution was then heated to 100°C and maintained there for 30 minutes before pouring onto ice (100 g). The pH is adjusted to 6 using 5M NaOH followed by extraction with dichloromethane (3 x 200 ml). The extracts were pooled, dried (over MgSO4) and concentrated under reduced pressure, giving (R)-aminoglutethimide (1.75 g, 97%) as a brown oil. Chiral HPLC analysis (Chiralcel OJ column; mobile phase 1:1 n-heptane- isopropanol) indicated an ee of 78%.
Example 4A 2-(4-Nitrophenyl)butyronitrile
A 3-necked round-bottomed flask was charged with cone. HNO3 (240 ml) and cooled to 10°C with the aid of an ice/acetone bath. Cone. H2SO4 (240 ml) was then added slowly so as to maintain the temperature below 30°C. 2-Phenylbutyronitrile (Aldrich, 110 ml) was introduced
dropwise to the stirred solution over a period of 1 hour, maintaining the temperature below 20°C. The ice/acetone bath was then removed and the mixture stirred for a further 30 minutes at ambient temperature before pouring it onto crushed ice (100 g). The resulting mixture was extracted with ethyl acetate (1500 ml x 2) and the extracts pooled, washed with saturated bicarb. (1000 ml) and water (500 ml). After drying over MgSO, the ethyl acetate was evaporated under reduced pressure to give crude 2-(4-nitrophenyl)- butyronitrile as a yellow oil, crude yield 138 g, 98%. Analysis by GC.MS indicated a para:meta ratio of 3.5:1. Example 4B Methyl 4-cyano-4-(4-nitrophenyl)hexanoate
A mixture of 2-(4-nitrophenyl)butyronitrile (10.0 g), butanol (10 ml) and methyl acrylate (5.2 ml) was cooled to 10°C in a 100 ml 3-necked round-bottomed flask, equipped with a magnetic follower. A solution of potassium tert- butoxide (0.6 g) in tert-butanol (10 ml) was added dropwise, maintaining the temperature at approximately 10°C (solution turns purple). After addition was complete, the mixture was allowed to reach ambient temperature and then stirred for a further 2 hours. The reaction was worked-up by partitioning between diethyl ether (400 ml) and 1 M KH2PO4 (400 ml). The ether layer was washed with water (50 ml), dried (MgSO4) and concentrated under reduced pressure to yield methyl 4-cyano-4-(4-nitrophenyl)hexanoate (14.1 g, 99%) as an orange oil.
Example 5
A l l jacketed biotransformation vessel was charged with 0.05 M KH2PO4, pH 7.5 (500 ml) and methyl 4-cyano-4-(4- nitrophenyl)hexanoate (20 g, 72 mmol). α-Chymotrypsin (ex. Aldrich; 4 g) was introduced and the mixture was agitated using an overhead stirrer. Temperature was maintained at 37°C with the aid of a thermocirculator and the pH controlled by a probe linked to an autotitrator. The biotransformation was allowed to proceed until 18 ml of IM NaOH had been added (equivalent to 50% conversion). This took about 68 hours, with addition of more α-chymotrypsin
(1 g portions) after 24 hours and 50 hours. At this point, the biotransformation was quenched by the addition of NaCl (50 g) and the resulting mixture was extracted with diethyl ether (500 ml x 3). The extracts were pooled, dried and concentrated under reduced pressure, yielding 10 g (50%) of (R)-methyl4-cyano-4-(4-nitrophenyl)hexanoate, enriched in the (R)-enantiomer, 70% ee by chiral HPLC analysis.
Example 6 Nitroglutethimide
(R)-methyl 4-cyano-4-(4-nitrophenyl)hexanoate (Example 5; 10 g, 36 mmol), enriched in the (R)-enantiomer to approximately 70% ee, was dissolved in glacial acetic acid (30.0 ml) contained in a 25 ml round-bottomed flask. The resulting mixture was heated to 60°C with the aid of an oil bath followed by dropwise addition of cone. H2SO4 (15.0 ml). The solution was then heated at 100°C for 30 minutes before pouring onto ice (100 g). The pH was adjusted to 6 using 5M NaOH and the mixture was then extracted with dichloromethane (3 x 200 ml). The extracts were pooled, dried (over MgSO4) and concentrated under reduced pressure, giving (R)-nitroglutethimide of approximately 70% ee (8.3 g, 88%) as a brown oil.
Example 7 (R)-Aminoglutethimide
A 3-necked round-bottomed flask was charged with (R)- nitroglutethimide (ca. 70% ee, 8.3 g, 32 mmol), 90% ethanol (250 ml) and PtO2 (0.35 g). The vessel was then evacuated and charged with nitrogen. The mixture was stirred vigorously and subjected to H2 at atmospheric pressure supplied via a balloon. The catalyst was removed by filtration through celite and the solvent removed under reduced pressure to give (R)-aminoglutethimide (ca. 70% ee, 7.1 g, 96%) as a pale brown solid.
Example 8
A loopful of Candida rugosa, ATCC 10571, was used to inoculate 50 ml of sterile pH 6.0 aqueous medium [containing (g/l) yeast extract (5), (NH4)2SO4 (1), KH2PO4 (5), MgSO4.7H2O (0.2) and glucose (10)] in 500 ml Erlenmeyer flasks shaken at 250 rpm with a one inch (25 mm) throw for
24 hours at 25°C. The cells were then harvested by centrifugation at 1200 g for 10 minutes. The cells were resuspended to one fifth of their original harvest volume in 50 mM potassium phosphate pH 6.0. A 50 mg/ml emulsion of ethyl 4-cyano-4-(4-nitrophenyl)hexanoate in 50 mM potassium phosphate + 0.1% Tween 80 was prepared by sonication for 10 minutes (cycles of 10 seconds on, 3 seconds off) at an amplitude of 18 μm in a Soniprep 150. 400 μl of this substrate emulsion was added to 1.6 ml of the resuspended cells in a 20 ml glass vial. The biotransformation reaction mixture was then incubated with shaking at 25°C, 250 rpm for 69 hours. After this time the reaction was stopped by the addition of 2 ml ethyl acetate. The sample was then analysed for enantiomeric excess by chiral HPLC (Chiralpak AD column; mobile phase 98.3% heptane-1.7% isopropyl alcohol; flow rate was 2 ml/min). The quenched reaction mixture was shaken vigorously and allowed to separate and the ethyl acetate layer pipetted off. Anhydrous magnesium sulphate was added. The dried ethyl acetate was transferred to a fresh vial and 25 μl trimethylsilyl diazomethane was added. The sample was mixed and left to stand for an hour at ambient temperature prior to HPLC analysis, which indicated >99% ee (R)-4- cyano-4-(4-nitrophenyl)hexanoic acid was produced in the biotransformation, with residual substrate ee of 24%, conversion 19%.
Example 9
Fusarium oxysporum IMI 329662 was cultured on 25 ml of sterile ptt 6.0 aqueous medium [containing (g/l) yeast extract (20), (NH4)2SO4 (4), KH2PO4 (5), MgSO4.7H2O (0.3) , Na2HPO4.2H2O (5), CaCl2.2H2O (0.2) and glucose (40) ], in 250 ml point-baffled Erlenmeyer flasks shaken at 250 rpm with a one inch (25 mm) throw for 72 hours at 25°C. Cells were harvested, resuspended to original volume in 50 mM potassium phosphate and used in biotransformation as in Example 8. The biotransformation was stopped after 24 hours and chiral HPLC analysis was carried out as described in
Example 8. This indicated 95.9% ee (R)-4-cyano-4-(4- nitrophenyl)hexanoic acid was produced in the biotransformation.
Example 10
Penicillium pinophilum IMI 114933 was cultured as described in Example 9 but with the inclusion of 10 g/1 tributyrin in the medium. Cells were harvested, resuspended to original volume in 50 mM potassium phosphate and used in biotransformation as in Example 8. The biotransformation was stopped after 24 hours and chiral HPLC analysis was carried out as described in Example 8. This indicated 89% ee (R)-4-cyano-4-(4-nitrophenyl)- hexanoic acid was produced in the biotransformation.
Claims (18)
1. A method for preparing, in the form of at least predominantly one enantiomer thereof, a chiral compound of formula I
wherein X and Z are each H or an organic group and Y is a cyclic group, which comprises cyclising a corresponding enantiomeric form of a chiral compound of formula II
wherein R is H or an esterifying radical.
2. A method according to claim 1, wherein X is C1-10 alkyl and R is H or C1-10 alkyl.
3. A method according to claim 2, wherein X is ethyl.
4. A method according to any preceding claim, wherein R is methyl or ethyl.
5. A method according to any preceding claim, wherein Z is H.
6. A method according to any preceding claim, wherein Y is 4-pyridyl, phenyl, 4-nitrophenyl or optionally N-protected 4-aminophenyl.
7. A method according to claim 1, wherein Y is 4- nitrophenyl, and which comprises the additional step of reduction, to give the corresponding compound wherein Y is 4-aminophenyl.
8. A method according to any preceding claim, wherein the compound of formula I is (R)-4-pyridoglutethimide or (R)- aminoglutethimide.
9. A method according to any preceding claim, wherein the compound of formula I is an aromatase inhibitor.
10. A method according to any preceding claim, wherein cyclisation comprises heating in an acidic medium.
11. A method according to any preceding claim, which comprises the prior steps of contacting racemic formula II compound, wherein R is not H, with an enantiospecific esterase; further resolution (if desired); and separating the compound of formula II from the acid formed by the esterase reaction.
12. A method according to claim 11, wherein the esterase has the characteristics of a protease such as α-chymotrypsin or that obtainable in Ophiostoma novo-ulmi , IMI 356050.
13. A method according to claim 11 or claim 12, wherein further resolution is conducted, using a camphorsulphonate salt or other resolution agent.
14. A compound of formula II as defined in any of claims 1 to 9 in the form of one enantiomer substantially free of the other enantiomer.
15. A compound according to claim 14, wherein the one enantiomer is the (R)-enantiomer.
16. A compound according to claim 14 or claim 15, wherein X is ethyl and Y is as defined in claim 6.
17. (R)-3-ethyl-3-(4-nitrophenyl)piperidine-2, 6-dione (nitroglutethimide) .
18. A compound according to any of claims 14 to 17, in an enantiomeriσ excess of at least 50%.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9410721A GB9410721D0 (en) | 1994-05-27 | 1994-05-27 | Chiral compounds and their resolution |
GB9410721 | 1994-05-27 | ||
PCT/GB1995/001228 WO1995032947A1 (en) | 1994-05-27 | 1995-05-30 | Chiral compounds and their resolution |
Publications (1)
Publication Number | Publication Date |
---|---|
AU2572495A true AU2572495A (en) | 1995-12-21 |
Family
ID=10755860
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU25724/95A Abandoned AU2572495A (en) | 1994-05-27 | 1995-05-30 | Chiral compounds and their resolution |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP0763023A1 (en) |
JP (1) | JPH10500861A (en) |
CN (1) | CN1151731A (en) |
AU (1) | AU2572495A (en) |
CA (1) | CA2191363A1 (en) |
FI (1) | FI964709A0 (en) |
GB (1) | GB9410721D0 (en) |
NO (1) | NO965551L (en) |
WO (1) | WO1995032947A1 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1167348A4 (en) | 1999-03-16 | 2002-11-13 | Eisai Co Ltd | Nitrile derivatives |
CA2377762C (en) | 1999-07-06 | 2008-09-30 | Methylgene Inc. | Sulfonamidomethyl phosphonate inhibitors of .beta.-lactamase |
US6884791B2 (en) | 1999-07-06 | 2005-04-26 | Methylgene, Inc. | Inhibitors of β-lactamase |
WO2006128590A1 (en) * | 2005-05-31 | 2006-12-07 | Dsm Ip Assets B.V. | Hydrolases, nucleic acids encoding them and methods for making and using them |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2848455A (en) * | 1955-07-18 | 1958-08-19 | Ciba Pharm Prod Inc | Alpha-(p-amino-phenyl)-alpha-lower alkyl glutarimides |
DE3724520C2 (en) * | 1986-07-31 | 1996-01-11 | Madaus Ag | New 3-aryl-3-cycloalkyl-piperidine-2,6-dione derivatives |
CA2116108A1 (en) * | 1991-08-22 | 1993-03-04 | Christopher T. Evans | Chiral gultarate esters, their resolution and derived glutarimide compounds |
-
1994
- 1994-05-27 GB GB9410721A patent/GB9410721D0/en active Pending
-
1995
- 1995-05-30 WO PCT/GB1995/001228 patent/WO1995032947A1/en not_active Application Discontinuation
- 1995-05-30 EP EP95920162A patent/EP0763023A1/en not_active Withdrawn
- 1995-05-30 JP JP8500505A patent/JPH10500861A/en active Pending
- 1995-05-30 CA CA 2191363 patent/CA2191363A1/en not_active Abandoned
- 1995-05-30 AU AU25724/95A patent/AU2572495A/en not_active Abandoned
- 1995-05-30 CN CN 95193815 patent/CN1151731A/en active Pending
-
1996
- 1996-11-26 FI FI964709A patent/FI964709A0/en not_active Application Discontinuation
- 1996-12-23 NO NO965551A patent/NO965551L/en unknown
Also Published As
Publication number | Publication date |
---|---|
JPH10500861A (en) | 1998-01-27 |
WO1995032947A1 (en) | 1995-12-07 |
EP0763023A1 (en) | 1997-03-19 |
GB9410721D0 (en) | 1994-07-13 |
FI964709A (en) | 1996-11-26 |
CA2191363A1 (en) | 1995-12-07 |
NO965551D0 (en) | 1996-12-23 |
FI964709A0 (en) | 1996-11-26 |
CN1151731A (en) | 1997-06-11 |
NO965551L (en) | 1997-01-09 |
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