GB2309224A - Isomers of tamoxifen and analogues thereof - Google Patents
Isomers of tamoxifen and analogues thereof Download PDFInfo
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- GB2309224A GB2309224A GB9618775A GB9618775A GB2309224A GB 2309224 A GB2309224 A GB 2309224A GB 9618775 A GB9618775 A GB 9618775A GB 9618775 A GB9618775 A GB 9618775A GB 2309224 A GB2309224 A GB 2309224A
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- tamoxifen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/32—Antioestrogens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Endocrinology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
TAMOXIFEN AND ANALOGUE8 THEREOF
This invention relates to tamoxifen and analogues thereof and particularly, although not exclusively, relates to a method of preparing a desired isomer of tamoxifen or an analogue thereof.
Tamoxifen is a triphenylethylene derivative of formula
which is a drug in clinical use for the treatment of hormone dependent breast cancer. For this purpose, only the Z isomer has the required antiestrogenic activity, the
E isomer being oestrogenic. The same criteria of antioestrogenecity applies to tamoxifen analogues. One of the most important analogues of tamoxifen is 4hydroxytamoxifen (one of the main metabolites in patients), which has an affinity for binding to oestrogen receptors which is 100 times higher than for tamoxifen itself. Accordingly, processes for stereoselective synthesis and/or isolation of substantially pure Z isomer of tamoxifen, 4-hydroxytamoxifen and other analogues are desirable.
Known processes for the preparation of substantially pure Z isomer of tamoxifen and 4-hydroxytamoxifen include stereoselective syntheses (involving expensive catalysts) as described in J. Chem. Soc., Perkin Trans I 1987, 1101 and J. Org. Chem. 1990, 55, 6184 or chromatographic separation of an E/Z mixture of isomers as described in J.
Chem. Res., 1985 (S) 116, (M) 1342, 1986 (S) 58, (M) 771.
It is an object of the present invention to provide a method of preparing a relatively pure isomer of tamoxifen or an analogue thereof which may be advantageous over known methods.
The invention is based on the surprising, and previously unappreciated, discovery that one geometric isomer of tamoxifen or an analogue thereof can be converted into another geometric isomer by contacting the isomer with certain solvents.
According to the invention, there is provided a method of preparing a first geometric isomer of tamoxifen or an analogue thereof, the method including selecting a solvent in which a second geometric isomer of tamoxifen or said analogue converts to said first geometric isomer and contacting said second geometric isomer with said solvent in order to cause said conversion.
The conversion of said second isomer to said first isomer can readily be shown using 1H NMR or other analytical techniques.
Preferably, the method comprises contacting a mixture which comprises said first and second isomers with said solvent.
Preferably, said method includes allowing said first geometric isomer to crystallise in said solvent. The method may include separating the crystallised product from the remainder.
Various solvents or mixtures of solvents may be selected for use in the method.
Preferably, the solvent is an organic solvent with polar organic solvents being preferred.
Said solvent is preferably a protic solvent.
Preferably, the solvent includes at least one, preferably only one, -OH group.
Said solvent is preferably an alcohol, preferably an aliphatic alcohol. An aliphatic alcohol may be a Ct to C12 alcohol, preferably a Cg to C6 alcohol, more preferably a Cs to C4 alcohol.
Preferably, the solvent is selected from methanol and propanol, especially iso-propanol. A mixture of methanol and propanol has been found to be particularly advantageous.
The method may be carried out at a temperature of less than 1000C, preferably less than 600C, more preferably less than 300C. Advantageously, the method may be carried out at ambient temperature or below.
Preferably, the method is carried out at a temperature of at least -100C and, more preferably, at least OOC.
Various analogues of tamoxifen which fall within the scope of the present invention are described in Endocrine
Reviews, 11(4), 1990, 578-603.
Analogues of tamoxifen may include optionallysubstituted triphenylalkyl or alkylene compounds.
Preferred optionally-substituted triphenyl compounds are of general formula
wherein A, B and P each independently represents an optionally-substituted phenyl group and Q represents a hydrogen atom or an optionally-substituted alkyl, alkenyl, alkynyl or phenyl group; and wherein a pair of adjacent substituents A, B, P and Q are optionally arranged together to form part of a ring structure.
It will be appreciated that the compound of general formula I may exist in different geometric isomeric forms and the formula is not intended, unless otherwise stated herein, to be limited to any such form.
Optional substituents as described herein include any substituents generally used to affect the activity of drugs for oral administration. In relation to alkyl, alkenyl, alkynyl and phenyl groups, preferred optional substituents include halogen atoms and a hydroxy group and optionally-substituted alkylcarboxy, alkoxy, phenoxy, alkylamino and alkylcarbonyl groups.
Preferred alkyl, alkenyl and alkynyl groups may have up to 12, preferably up to 6, more preferably up to 4 carbon atoms.
Preferably, Q represents an optionally-substituted, preferably unsubstituted, alkyl group. Preferably, said alkyl group is a C1 to C4, more preferably a C1 to , alkyl group. Q preferably represents an ethyl group.
Preferably, groups A, B and P independently represent an unsubstituted or monosubstituted phenyl group. Where a group A, B or P is substituted, it is preferably substituted in the 3- or, more preferably, the 4position.
Preferably, group B is unsubstituted.
Group P is preferably unsubstituted or substituted by a halogen atom or hydroxy, optionally-substituted alkoxy or phenoxy, groups. Where group P is substituted, it is preferably substituted in the 4-position.
Preferably, group A is monosubstituted by a halogen atom or hydroxy, optionally-substituted alkoxy or phenoxy, groups. Preferably, group A is monosubstituted by an optionally-substituted alkoxy group. A preferred optionally-substituted alkoxy group is of general formula
-O-(CH2)n-X (II) wherein n represents an integer preferably in the range 1 to 8, more preferably 1 to 4; and
X represents a leaving group, for example a halogen, especially a chlorine, atom, or a group of general formula
wherein Rl and R2 independently represent a hydrogen atom or an optionally-substituted, preferably unsubstituted, alkyl group.
Preferably, n represents 2.
Preferably, said second geometric isomer contacted with solvent in the method is a first analogue of tamoxifen and the method includes the further step of derivatising the first geometric isomer prepared in order to prepare tamoxifen or a second analogue thereof. Thus, preferably the second geometric isomer contacted in the method is a precursor in the preparation of tamoxifen or said second analogue thereof. Preferably, the first analogue of tamoxifen contacted in the method, more preferably said first geometric isomer of said first analogue prepared in the method, has less antiestrogenic activity compared to tamoxifen or said second analogue.
Preferably, said precursor is a compound of general formula I described above wherein B, P and Q are as described above. Preferably, A represents a phenyl group substituted, preferably at the 4-position, by a first moiety which includes an active atom or group which is arranged to react with a second moiety which includes a group of general formula III as described above in order to produce an optionally substituted alkoxy group of general formula II as described above. Preferably, said first moiety includes a leaving group which is suitably X as described above. Preferably, said first moiety comprises a group of general formula II as described above. Said first moiety is preferably reacted with an amine of general formula R1R2NH wherein Rl and R2 are as described above.
Where a pair of adjacent substituents A, B, P and Q are arranged together to form part of a ring structure, the ring structure may be formed between pairs of substituents A, B, P and Q which are cis to one another.
Examples of compounds of general formula I which have ring structures as described include:
wherein Z represents an oxygen or sulphur atom or a group -CH2CH2-.
Preferably, adjacent substituents A, B, P and Q do not form part of a ring structure.
The ratio of the volume of the first and/or second isomers to the volume of the solvent used in the method may be in the range 0.1 to 10, preferably in the range 0.5 to 5 and more preferably about 1 to 1. Preferably, sufficient solvent is used to substantially dissolve the first and/or second isomers and thereby define a singlephase solution.
When the method involves contacting a mixture which comprises first and second isomers, the mixture used may be prepared by known routes to tamoxifen and its analogues, for example as described in J.Chem. Research, 1985(S) 116, (M) 1342 and 1986 (S) 58, (M) 0771.
A typical reaction scheme for preparing tamoxifen is as shown below in Scheme I.
Referring to Scheme I, preferably, the alkene derivative of formula XI is contacted with said solvent prior to the reaction with trimethylamine. In one embodiment, it is found that, after contacting a mixture of geometric isomers of said compound XI with methanol, tamoxifen can be produced which contains over 98 wt% of the desired Z isomer (which has the stereochemical configuration of compound XI shown in Scheme I) and 1-2 wt% of the undesired E isomer. Thus, in general terms, the method described above may be used to prepare tamoxifen or an analogue which includes greater than 95 wt% and preferably greater than 98 wt% of said first geometric isomer.
A typical process for preparing 4-hydroxytamoxifen involves derivatising compound X prepared according to the reaction scheme provided below.
The invention extends to a method of preparing tamoxifen or an antiestrogenic analogue thereof, the method including the steps of contacting a precursor of tamoxifen or said analogue with a solvent in which a second geometric isomer of said precursor can convert to a first geometric isomer thereof and derivatising said precursor in order to produce said tamoxifen or said analogue.
The invention extends to the use of a solvent for converting a second geometric isomer of tamoxifen or an analogue thereof into a first geometric isomer.
The invention extends to the product of any process described herein.
Any feature of any aspect or embodiment described herein may be combined with any feature of any other aspect or embodiment described herein.
The invention will now be described, by way of example, with reference to the accompanying figures wherein:
Figure 1 is a 'H NMR spectrum for a mixture of isomers of a tamoxifen precursor, prepared in Example 3;
Figures 2 to 4 provide further detail for the spectrum of Figure 1; and
Figure 5 is a 'H NMR spectrum for the product obtained in Example 3 after treatment with methanol.
Example 1
Preparation of 4-Hydroxytamoxifen A solution of 1,2-dibromoethane (1.41g, 7.5mmol) in ether (5ml) was added dropwise with stirring to a boiling solution of 2,3,5, 6-tetrafluoro-l-(4' -bromophenoxy) -4- (trifluoromethyl)benzene (3.89g), lOmmol) in ether (3ml) containing magnesium turnings (486mg, 20mmol) under dried nitrogen in order to prepare a Grignard reagent. When the addition was complete, a solution of 1-[4-(2 chloroethoxy) phenyl] -2-phenyl-1-butanone (compound VIII) (3.02g, 10mmol) in ether was added. The resulting mixture was stirred at room temperature for 20 hours. The solution was then poured into dilute hydrochloric acid (75ml) and extracted with ether (3x50ml).The combined ether extracts were dried, concentrated, redissolved in absolute alcohol (10ml) and ref fluxed with concentrated hydrochloric acid (3ml) for 4 hours. The solution was then poured into water (25ml) and extracted with ether (3x20ml). The organic extracts were dried and concentrated to give a light brown oil (about 7ml) which was dissolved in the same volume of methanol and left for 96 hours in a stoppered flask.
Crystals of E isomer of compound X separated out of solution. M.p. 114-1170C (lit. 116-1180C), m/z 594, #H 0.92 (3H, t, J = 7.51 Hz, CH3), 2.45 (2H, q, J = 7.51 Hz,
CH2CH3), 3.73 (2H, t, J = 5.86 Hz, OCH2CH2C1), 4.10 (2H, t,
J - 5.86 Hz, OCH2CH2C1), 6.57 (2H, d, J = 8.8 Hz, aromatic protons ortho to OCH2CH2C1), 6.77 (2H, d, J = 8.8 Hz, aromatic protons meta to OCH2CH2C1), 6.98 (2H, d, J = 8.61
Hz, aromatic protons ortho to OC7F7), 7.09-7.18 (SH, m,
C6H5), 7.22 (2H, d, J = 8.61 Hz, aromatic protons meta to OC7F). It was observed that recrystallisation of the E isomer from methanol was not possible.A typical yield for the E isomer starting from the ketone of formula VIII was 41%. The isolated E isomer of compound X can readily be converted to the desired oestrogenic isomer of 4hydroxytamoxifen as described in, for example, J. Chem.
Research, 1985 (S) 116, (M) 1342 and 1986 (S) 58, (M) 0771.
Example 2
Preparation of Z isomer of 4-Hvdroxvtamoxifen
The procedure of Example 1 was followed except that the oil produced was dissolved in a 2:1 mixture of methanol and i-propanol. It was observed that a 41% yield of the desired E isomer was obtained in 4 hours.
Example 3
Preparation of Z isomer of Tamoxifen
A solution of bromobenzene (3.92g, 25mmol) in ether (5ml) containing a crystal of iodine was added dropwise to a suspension of magnesium turnings (0.63g, 26mmol) in ether (5ml) at reflux, under nitrogen. After the addition was complete, the reaction mixture was cooled to room temperature and a solution of 1-[4-(2 chloroethoxy)phenyl)-2-phenyl-1-butanone (3. 75g, 12. 4mmol) in ether (15ml) was added over 1 hour. The resulting mixture was ref fluxed for 16 hours, then poured into dilute hydrochloric acid (50ml) and extracted with ether (3x40ml). The combined ether layers were concentrated, the residual oil was dissolved in ethanol (10ml) and ref fluxed with concentrated hydrochloric acid (5ml) for 4 hours.The organic phase was separated, dried (Na2SO4) and evaporated to dryness to give a yellow oil. 1H NMR (see Figures 1 to 4 and discussion below) showed this to be a 2:1 mixture of the Z and E isomers. The oil was then dissolved in warm methanol (about 400C) and allowed to cool to room temperature. The colourless crystals formed proved to be pure Z isomer of 2-chloroethoxy tamoxifen (4.12g, 11.4mmol, 92% yield).M.p. 107-1090C, m/z 362/364 (chlorine atom present), 5H 0.92 (3H, t, J = 7.33 Hz, CH3), 2.46 (2H, q, J = 7.33 Hz, CH2CH3), 3.72 (2H, t, J = 5.86 Hz, OCH2CH2Cl), 4.09 (2H, t, J - 5.86 Hz, OCH2CH2Cl), 6.55 (2H, d, J = 8.79 Hz, aromatic protons ortho to OCH2CH2C1), 6.79 (2H, d, J = 8.79 Hz, aromatic protons meta to OCHzCH2C1), 7.10-7.38 (10H, m, the two remaining CJ5's) (see Figure 5). The 2-chloroethoxy tamoxifen was reacted with dimethylamine in ethanol, under reflux, to produce the desired Z isomer of tamoxifen.
Analvsis of tH NMR data
Figures 1 to 4 represent a mixture of the E- and Zforms of compound XI described above.
The expansion of the region 6 0.80 to 1.05 shows two overlapping triplets corresponding to the CH3 groups in the
Z- and E- derivatives respectively. The critical point is the ratio of the heights of the peaks at 0.92 (for the Z) and 0.94 (for the E), which is approximately 2:1.
The expansion of the 4.00 to 4.35 region reveals similar information where ratios are 10:6.4 and 5.56:3.43.
Similarly expansion of the region 3.6 to 3.9 shows the ratio to be 2.46:1. All of these measurements suggest an approximate 2:1 ratio.
Referring to Figure 5, this shows almost pure Zisomer. It should be noted that there is 660 mg of this from an original mixture of a 2:1 ratio mixture of 780 mg which would contain only 520 mg of the Z-isomer.
The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.
All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.
Each feature disclosed in this specification (including any accompanying claims, abstract and drawings), may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.
The invention is not restricted to the details of the foregoing embodiment(s). The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.
Claims (14)
1. A method of preparing a first geometric isomer of tamoxifen or an analogue thereof, the method including selecting a solvent in which a second geometric isomer of tamoxifen or said analogue converts to said first geometric isomer and contacting said second geometric isomer with said solvent in order to cause said conversion.
2. A method according to Claim 1, comprising contacting a mixture which comprises said first and second isomers with said solvent.
3. A method according to Claim 1 or Claim 2, including allowing said first geometric isomer to crystallise in said solvent.
4. A method according to any preceding claim, wherein the solvent is an organic solvent.
5. A method according to any preceding claim, wherein the solvent is a polar organic solvent.
6. A method according to any preceding claim, wherein the solvent is a protic solvent.
7. A method according to any preceding claim, wherein said solvent is an alcohol.
8. A method according to any preceding claim, wherein the solvent is selected from methanol and/or propanol.
9. A method according to any preceding claim, carried out at a temperature of less than 100 C.
10. A method according to any preceding claim, wherein said analogues of tamoxifen include optionally substituted triphenylalkyl or triphenylalkylene compounds.
11. A method according to any preceding claim, wherein said second geometric isomer contacted with solvent in the method is a first analogue of tamoxifen and the method includes a further step of derivatising the first geometric isomer prepared in order to prepare tamoxifen or a second analogue thereof.
12. A method of preparing tamoxifen or an antiestrogenic analogue thereof, the method including the steps of contacting a precursor of tamoxifen or said analogue with a solvent in which a second geometric isomer of said precursor can convert to a first geometric isomer thereof and derivatising said precursor in order to produce tamoxifen or said analogue.
13. The use of a solvent for converting a second geometric isomer of tamoxifen or an analogue thereof into a first geometric isomer of tamoxifen or the same analogue.
14. A method substantially as hereinbefore described with reference to the examples.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97900379A EP0883587A1 (en) | 1996-01-20 | 1997-01-20 | Tamoxifen and analogues thereof |
| JP9525793A JP2000503315A (en) | 1996-01-20 | 1997-01-20 | Tamoxifen and its congeners |
| AU13953/97A AU725286B2 (en) | 1996-01-20 | 1997-01-20 | Tamoxifen and analogues thereof |
| PCT/GB1997/000134 WO1997026234A1 (en) | 1996-01-20 | 1997-01-20 | Tamoxifen and analogues thereof |
| CA002243330A CA2243330A1 (en) | 1996-01-20 | 1997-01-20 | Tamoxifen and analogues thereof |
| HU9900951A HUP9900951A3 (en) | 1996-01-20 | 1997-01-20 | Process for producing tamoxifen and analogues thereof |
| US09/118,836 US6172263B1 (en) | 1996-01-20 | 1998-07-20 | Tamoxifen and analogues thereof |
| NO19983346A NO311346B1 (en) | 1996-01-20 | 1998-07-20 | Tamoxifen and analogues thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9601167.1A GB9601167D0 (en) | 1996-01-20 | 1996-01-20 | Tamoxifen and analogues thereof |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB9618775D0 GB9618775D0 (en) | 1996-10-23 |
| GB2309224A true GB2309224A (en) | 1997-07-23 |
| GB2309224B GB2309224B (en) | 2000-06-28 |
Family
ID=10787311
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GBGB9601167.1A Pending GB9601167D0 (en) | 1996-01-20 | 1996-01-20 | Tamoxifen and analogues thereof |
| GB9618775A Expired - Fee Related GB2309224B (en) | 1996-01-20 | 1996-09-09 | Tamoxifen and analogues thereof |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GBGB9601167.1A Pending GB9601167D0 (en) | 1996-01-20 | 1996-01-20 | Tamoxifen and analogues thereof |
Country Status (1)
| Country | Link |
|---|---|
| GB (2) | GB9601167D0 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2327673A (en) * | 1997-07-23 | 1999-02-03 | Univ Bradford | Tamoxifen and analogues thereof |
| US6172263B1 (en) | 1996-01-20 | 2001-01-09 | Bradford University | Tamoxifen and analogues thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0127128A1 (en) * | 1983-05-24 | 1984-12-05 | Bristol-Myers Company | Process for the conversion of the E isomer of 1,2-diphenyl-1-(4-(2-dimethylaminoethoxy)-phenyl)-1-butene to tamoxifen HCl |
| EP0287690A1 (en) * | 1987-04-21 | 1988-10-26 | HEUMANN PHARMA GMBH & CO | Stable solvent adducts of Z-1-(p-beta-dimethylamino-ethoxyphenyl)-1-(p-hydroxyphenyl)-2-phenylbut-1-ene |
| WO1995011879A1 (en) * | 1993-10-25 | 1995-05-04 | Taiho Pharmaceutical Co., Ltd. | Process for producing acid-addition salt of z-isomer of triphenylethylene compound |
| WO1995018786A1 (en) * | 1994-01-03 | 1995-07-13 | Klinge Pharma Gmbh | Method for the production of e-1-[4'-(2-dimethylaminoethoxy)-phenyl]-1-(3'-hydroxyphenyl)-2-phenyl-1-butene |
-
1996
- 1996-01-20 GB GBGB9601167.1A patent/GB9601167D0/en active Pending
- 1996-09-09 GB GB9618775A patent/GB2309224B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0127128A1 (en) * | 1983-05-24 | 1984-12-05 | Bristol-Myers Company | Process for the conversion of the E isomer of 1,2-diphenyl-1-(4-(2-dimethylaminoethoxy)-phenyl)-1-butene to tamoxifen HCl |
| EP0287690A1 (en) * | 1987-04-21 | 1988-10-26 | HEUMANN PHARMA GMBH & CO | Stable solvent adducts of Z-1-(p-beta-dimethylamino-ethoxyphenyl)-1-(p-hydroxyphenyl)-2-phenylbut-1-ene |
| WO1995011879A1 (en) * | 1993-10-25 | 1995-05-04 | Taiho Pharmaceutical Co., Ltd. | Process for producing acid-addition salt of z-isomer of triphenylethylene compound |
| WO1995018786A1 (en) * | 1994-01-03 | 1995-07-13 | Klinge Pharma Gmbh | Method for the production of e-1-[4'-(2-dimethylaminoethoxy)-phenyl]-1-(3'-hydroxyphenyl)-2-phenyl-1-butene |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6172263B1 (en) | 1996-01-20 | 2001-01-09 | Bradford University | Tamoxifen and analogues thereof |
| GB2327673A (en) * | 1997-07-23 | 1999-02-03 | Univ Bradford | Tamoxifen and analogues thereof |
| GB2327673B (en) * | 1997-07-23 | 2002-03-27 | Univ Bradford | Tamoxifen and analogues thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2309224B (en) | 2000-06-28 |
| GB9601167D0 (en) | 1996-03-20 |
| GB9618775D0 (en) | 1996-10-23 |
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Effective date: 20060909 |