GB2158068A - Pyrimidine derivative solvate compounds - Google Patents
Pyrimidine derivative solvate compounds Download PDFInfo
- Publication number
- GB2158068A GB2158068A GB08510664A GB8510664A GB2158068A GB 2158068 A GB2158068 A GB 2158068A GB 08510664 A GB08510664 A GB 08510664A GB 8510664 A GB8510664 A GB 8510664A GB 2158068 A GB2158068 A GB 2158068A
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- Prior art keywords
- compound
- pyrimidine
- group
- derivative
- amino
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Molecular complexes in the form of solvates of an aminopyrimidine derivative and an N-alkylformamide, especially N-methylformamide (NMF) or dimethylformamide (DMF) are disclosed. The aminopyrimidine derivative is generally a diaminopyrimidine or an aminopyrimidinone having a formula (II): <IMAGE> where one of X and Y is an amino group and the other of X and Y is an amino group or -OH; R2 is a halogen, hydrogen or an alkyl group of 1-4 carbon atoms and R3 is an aryl or aralkyl group, or R2 and R3 together and including the part of the pyrimidine ring to which they are bonded form a six-membered ring having a general formula (III): <IMAGE> where Z is nitrogen or CH; R4 is alkyl; and R5 is a methoxy substituted phenyl group or a methoxy substituted anilino radical.
Description
SPECIFICATION
Pyrimidine derivative compounds
The present invention relates to novel compounds of pyrimidine derivatives and pharmaceutical formulations thereof. The pyridimine derivatives in question are generally pharmacologically active and comprise derivatives recognised to have antitumour, antimalarial, antipsoriatic, antibacterial, antiviral, immunomodulatory or interferon-inducing activity. and may be either aminopyrimidinones or diaminopyrimidines as hereinafter specified.
Certain aminopyrimidinones such as for example 2-amino-5-bromo-6-phenylpyrimidin-4(3H)-one (ABPP) and derivatives thereof are already known to have useful antitumour or other pharmacological properties.
An original report on the synthesis of ABPP was published by T. B. Brown and M. F. G. Stevens (JCS Perkin I, 1975, 1023) and the discovery that ABPP has interferon-inducing properties, immunomodulatory activity and antiviral activity was published by W. Wierenga petal (J. Medicin. Chem., 1980,23,237). Additional information on the interferon-inducing activity of ABPP and analogues has been reported later by W.
Wierenga, (Annual Reports in Medicinal Chemistry, 1982, 17, 151-161). It has also been found by M.F.G.
Stevens that ABPP has antitumour activity against the B16 melanoma and M5076 reticulum cell sarcoma growing in mice.
The structures of ABPP and an analogue 2-amino-5-bromo-6-(2-fluorophenyl)-pyrimidin-4(3H)-one (ABoFPP) are depicted below:
Another example of an aminopyrimidinone which exhibits pharmacological activity is 4-amino-5-(3-nitro- 4-piperidinophenyl)-6-ethyl pyrimidin-2(1 H)-one.
It is also known that many diaminopyrimidine derivatives are pharmacologically active. For example, pyrimethamine (2,4-Diamino-5-(4-chlorophenyl)-6-ethylpyrimidine), aminopyrimethamine (2,4-Diamino-5 (3-amino-4-chlorophenyl)-6-ethylpyrimidine), nitropyrimethamime (2,4-Diamino-5-(4-chloro-3-nitrophenyl)6-ethylpyrimidine) and Metoprin (2,4Diamino-5-(3,4-dichlorophenyl)-6-methylpyrimidine) are recognised as being useful antitumour and antimalarial agents, Trimetrexate (2,4-Diamino-5-methyl-6-[(3,4,5trimethoxyanilino)-methyl)]quinazoline) and the compound supplied by The Wellcome Foundation under the designation BW 301 U (2,4-Diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine) are recognised as having antitumour and/or antipsoriatic activity, whilst Trimethoprin (2,4-Diamino-5-(3,4,5 trimethoxy)benzyl pyrimidine) is recognised as having antibacterial activity.
It has now been found that many such pyrimidine derivatives, in particular aminopyrimidine derivatives, will combine or associate with N-alkylformamides to form solvates constituting molecular complexes representing novel compounds, and these novel compounds may have particularly useful pharmacological or chemotherapeutic properties.
Thus, when aminopyrimidine derivatives, which may be either aminopyrimidinones or diaminopyrimidines, in accordance with this invention are dissolved in an N-alkylformamide, especially N-methylformamide (NMF) or dimethylformamide (DMF), solvates can be produced which can be isolated to provide new compounds that may incorporate, combine or enhance the properties of the individual constituents.
For example, this formation or production of a solvate can lead to new pharmaceutical substances or compositions and formulations which will combine the antitumour or other pharmacological attributes of the aminopyrimidine derivative with complementary attributes of the N-alkylformamide constituent. It can also lead to improved solubility and/or improved potential for formulation and for convenient or efficient administration and/or improved stability and/or improved therapeutic efficacy of the pharmacologically active constituent.
It will be appreciated that the formation of such solvates represents generally the formation of molecular complexes of definite constitution and structure.
In a broad aspect, the present invention accordingly provides as a novel compound a solvate constituting a molecular complex of an aminopyrimidine derivative and an N-alkylformamide.
In preferred embodiments, the N-alkylformamide is N-methylformamide (NMF) or dimethylformamide (DMF) and the aminopyrimidine derivative is an aminopyrimidinone or a diaminopyrimidine having a general formula (ill):
where one of X and Y is an amino group and the other of X and Y is an amino group or -OH; R2 is a halogen, hydrogen or an alkyl group of 1-4 carbon atoms and R3 is an aryl or aralkyl group, or R2 and R3 together and including the part of the pyrimidine ring to which they are bonded form a six-membered ring having a general formula (III):
where Z is nitrogen or CH; R4 is alkyl; and R5 is a methoxy substituted phenyl group or a methoxy substituted anilino radical.
Usefully, R3 is a substituted phenyl group having the general formula (IV):
where A and B are the same or different and are selected from hydrogen, halogen, -NH2, -NO2, akoxy or piperidino.
In general, the molecular ratio of the constituents of the molecular complex constitutors the solvate will be in the range of 1:1 to 1:3. In particular, the molecular ratio of the aminopyrimidine derivative to
N-alkylformamide in the solvate may be 2:1, 1:1 or 1:3.
The invention will now be further described by reference to the following Examples:
Example 1 (ABPP-NMFsolvate) 0.5 grams of 2-Amino-5-bromo-6-phenylpyrimidin-4(3H)-one (ABPP) was dissolved in 13 mls. of
N-methylformamide (NM F) by heating on a steam bath at 1 000C. The solution was filtered, then allowed to crystallise (3 days) and the colourless crystalline solid thus obtained was collected, rinsed with chloroform and dried for 3 days at 65"C. The product was a solvate of ABPP and N-methylformamide having the constitution ABPP (2 molecules):NMF (1 molecule) and had melting-point 190-195"C (with sintering) followed by decomposition over the temperature range 280-285"C.
An X-ray crystallographic analysis of the solvate showed that the two molecules of ABPP are hydrogen-bonded together, as indicated in Figure 1 of the accompanying drawing, in the manner of a
Watson-Crick cytosine:guanine base pair.
Example2 (ABoFPP- NMFSolvate) 2-Amino-5-bromo-6-(2-fluorophenyl)-pyrimidin-4(3H)-one (ABoFPP) (0.6 grams) was similarly crystallised from a solution of N-methylformamide as in Example 1 and formed colourless crystals of a solvate. In this case the solvate had the constitution of 2-amino-5-bromo-6-(2-fluorophenyl)-pyrimidin-4(3H)-one (2 molecules): NMF (1 molecule) and'had a melting point 175-180"C (with sintering) followed by decomposition over the temperature range 290-300"C.
Example 3 rPyrimethamine-NMFsolvate) 2,4-Diamino-5-(4-chlorophenyl)-6-ethylpyrimidine (pyrimethamine) (0.5 g) was crystallised from hot
N-methylformamide (NMF) (30 ml). The solution was filtered and allowed to cool whereupon colourless prisms of pyrimethamine: NMF solvate in a 1:2 molar ratio were formed, m.p. 241-243"C (with sintering at 180"C). The solvate was characterised by its nmr spectrum (in trifluoroacetic acid/deuteriochloroform):
1.20(3H, triplet, CH3), 2.4(2H, quartet, CH2), 2.95(6H, doublet, HCONHCH3), 6.20(2H, broad singlet, HCONHCH3), 7.3(4H, multiplet, aromatic H), 8.15(2H, broad singlet, HCONHCH3).
Example 4 (Nitrop yrimethamine-NMF solvate) 2,4-Diamine-5-(4-chloro-3-nitrophenyl)-6-ethylpyrimidine (nitropyrimethamine) (0.5 9) was crystallised from hot N-methylformamide (NMF) (3 ml). Yellow crystals of nitropyrimethamine:NMF solvate in a 1:1 molar ratio were formed, m.p.2315C.
(Found: C, 46.82; H, 4.37; N, 23.85.
C12H12CIN50.C2H5NO requires C, 46.67; H, 4.86; N, 23.82%).
Example 5 (Metoprin-NMFsolvate) 2,4-Diamino-5-(3,4-dichlorophenyl)-6-methylpyrimidine (metoprin) (0.5 9) was crystallised from hot
N-methylformamide (NMF) (5 ml) to afford white crystals of metoprin: NMF solvate (1:1 molar ratio), m.p.
280 C. (Found C, 47.43; H, 4.27; N,21.00.
C11 H10Cl2N4.C2H5NO requires C, 47.58; H, 4.61; N, 21.34%).
Example 6 (Aminopyrimethamine-NMFsolvate) 2,4-Diamino-5-(3-amino-4-chlorophenyl)-6-ethylpyrimidine (aminopyrimethamine) (0.5 9) was crystallised from hot N-methylformamide (NMF) (7 ml) to yield white crystals of aminopyrimethamine:NMF solvate (1:1 molar ratio), m.p. 200"C. (Found: C, 50.40; H, 6.31; N, 25.54.
C12H14ClN5.C2H5NO requires C, 50.33; H, 6.33; N, 25.68%).
Example 7 (Nitrop yrimethamine DMF-solvatel
Crystallisation of 2,4-Diamino-5-(4-chloro-3-nitrophenyl)-6-ethylpyrimidine (nitropyrimethamine) (0.5 g) from dimethylformamide (10 mIs) afforded thick yellow needles of nitropyrimethamine dimethylformamide solvate (1 :1 molar ratio), m.p. 222-225"C (sinters 175"C). (Found: C, 49.3; H, 5.4; N, 23.1.
C12H12C1N5O2.C3H7NO requires C, 49.1; H, 5.2; N, 22.9%).
Example 8 (ABPP-DMFsolvate) Crystallisation of 2-Amino-5-bromo-6-phenyl pyrimidin-4(3H)-one (ABPP) (0.5 9) from dimethylformamide (5 mIs) afforded white crystals of ABPP dimethylformamide solvate (1:1 molar ratio), m.p. 245"C (Found: N, 16.31. C10H8BrN3O.C3H7NO requires N, 16.53%).
Example 9 (2,4-Diamino-6-ethyl-5-(3-nitro-4-piperidinophenyl)pyrimidine-DMF solvate)
A sample of 2,4-Diamino-6-ethyl-5-(3-nitro-4-piperidinophenyl)pyrimidine (0.5 g) crystallised from dimethylformamide (5 mls) as a tri-dimethylformamide solvate (C,7H22N602. 3 X C3H7NO), m.p. 248-25"C, in the form of yellow crystals.
Example 10(4-A mino-5-(3-nitro-4-piperidinophenyl)-6-ethylpyrimidin-2( lH)-one DMF solvate) A sample of 4-amino-5-(3-nitro-4-piperidinophenyl)-6-ethylpyrimidin-2(1 H)-one (0.5 g) was crystallised from a mixture of dimethylformamide (5 mls) and ethanol (5 mls) to afford yellow crystals of a tri-dimethylformamidesolvate, m.p. 294-296"C, (C17H21N5O3. 3 x C3H7NO).
For therapeutic use in the treatment of mammals, while it is possible for the solvates provided by the present invention to be administered alone as the active compound, it is preferable to present them as a pharmaceutical formulation. Formulations of the present invention, for medical use, thus comprise the active solvate compound together with one or more pharmaceutically acceptable carriers thereof and, optionally, any other therapeutic ingredients. The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include generally the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. Usually, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or with a finely divided solid carrier or with both and then, if necessary, shaping the product into desired formulations.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or a suspension in an aqueous liquid or non-aqueous liquid such as a syrup, an elixir, an emulsion or a draught. The active compound may also be presented as a bolus, electuary or paste, or in creams or ointments for topical use.
Atablet may be made by compression or moulding, optionally with one or more accessory ingredients.
Compressed tablets may be prepared by compressing, in a suitable machine, the active compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active compound with any suitable carrier.
A syrup may be made by adding the active compound to a concentrated, aqueous solution of a sugar, for example sucrose, to which may be added any accessory ingredient. Such accessory ingredient(s) may include flavourings, an agent to retard crystallisation of the sugar or an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol for example glycerol orsorbitol.
Formulations for rectal administration may be presented as a suppository with a usual carrier such as cocoa butter.
Formulations suitable for parental administration conveniently comprise a sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient.
In addition to the aforementioned ingredients, the formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
Overall, the invention comprises each and any novel feature or combination of features disclosed herein.
Claims (22)
1. As a novel compound a solvate constituting a molecular complex of an aminopyrimidine derivative and an N-alkylformamide.
2. A compound as claimed in Claim 1 wherein the N-alkylformamide has the general formula (I):
where R1 is hydrogen or CHB.
3. A compound as claimed in Claim 2 wherein the aminopyrimidine derivative has a general formula (ill):
where one of X and Y is an amino group and the other of X and Y is an amino group or -OH; R2 is a halogen, hydrogen or an alkyl group of 1-4 carbon atoms and R3 is an aryl or aralkyl group, or R2 and R3 together and including the part of the pyrimidine ring to which they are bonded form a six-membered ring having a general formula (III):
where Z is nitrogen or CH; R4 is alkyl; and R5 is a methoxy substituted phenyl group or a methoxy substituted anilino radical.
4. A compound as claimed in Claim 3 wherein R3 is a substituted phenyl group having the general formula (IV):
where A and B are the same or different and are selected from hydrogen, halogen, alkoxy, - NH2, -NO2, or piperidino.
5. A compound as claimed in any of the preceding claims wherein the pyrimidine derivative is an aminopyrimidinone.
6. A compound as claimed in Claim 5 insofar as it is dependent on Claim 4, wherein R2 is a halogen in the 5-position of the pyrimidine ring and R3 is a phenyl group or a halogen substituted phenyi group in the 6-position of the pyrimidine ring.
7. A compound as claimed in any of the preceding claims wherein the pyrimidine derivative is 2-Amino-5-bromo-6-phenyl pyrimidin-4(3H)-one or 2-Amino-5-bromo-6-(2-fluorophenyl)pyrimidin-4(3H) one.
8. A compound as claimed in any of claims 1 to 4 wherein the pyrimidine derivative is a diaminopyrimidine.
9. A compound as claimed in Claim 8 insofar as it is dependent on Claim 4, wherein R2 is a methyl or ethyl group in the 6-position of the pyrimidine ring and R3 is a substituted phenyl group in the 5-position of the pyrimidine ring.
10. A compound as claimed in Claim 9 wherein at least the substituentA in the phenyl group is halogen.
11. A compound as claimed in any of Claims 8 to 10 wherein the pyrimidine derivative is pyrimethamine, aminopyrimethamine, nitropyrimethamine or Metoprin.
12. A compound as claimed in Claim 8 insofar as it is dependent on Claim 3, wherein R2 is hydrogen and
R3 is a methoxy substituted benzyl radical.
13. A compound as claimed in Claim 12 wherein the pyrimidine derivative is Trimethoprin.
14. A compound as claimed in any of Claims 1 to 3 wherein the amino pyrimidine derivative is 2,4-Diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl)]quinazoline (trimetrexate) or 2,4-Diamino-6-(2,5 dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine (BW301 U).
15. A compound as claimed in any of the preceding claims wherein the molecular ratio of the constituents in the molecular complex constituting the solvate is in the range of 1:1 to 1:3.
16. As a novel compound of solvate of an aminopyrimidine derivative and an alkylformamide substantially as herein described in, and with reference to, any one of Examples 1 to 10.
17. A compound as claimed in any of the preceding claims fortherapeutic use as an active antitumour, antimalarial, antipsoriatic, antibacterial, antiviral or immunomodulatory agent in treating mammals.
18. A compound as claimed in Claim 17 in unit dosage form made up for administration to the mammal.
19. A compound as claimed in Claim 17 in combination with a pharmaceutically acceptable carrier or vehicle.
20. A pharmaceutical formulation for medical use comprising, as the active compound, a compound as claimed in any one of Claims 1 to 16 together with a pharmaceutically acceptable carrier therefor.
21. A method of preparing a pharmaceutical formulation as specified in Claim 20, said method comprising the step of bringing the said active compound into association with said carrier which constitutes one or more accessory ingredients.
22. Use of a compound as claimed in any of Claims 1 to 16 for the manufacture of a medicament for antitumour, antimalarial, antipsoriatic, antibacterial, antiviral or immunomodulatory therapy of mammals.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB848410636A GB8410636D0 (en) | 1984-04-26 | 1984-04-26 | Pharmaceutical substances/compositions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB8510664D0 GB8510664D0 (en) | 1985-06-05 |
| GB2158068A true GB2158068A (en) | 1985-11-06 |
Family
ID=10560099
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB848410636A Pending GB8410636D0 (en) | 1984-04-26 | 1984-04-26 | Pharmaceutical substances/compositions |
| GB08510664A Withdrawn GB2158068A (en) | 1984-04-26 | 1985-04-26 | Pyrimidine derivative solvate compounds |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB848410636A Pending GB8410636D0 (en) | 1984-04-26 | 1984-04-26 | Pharmaceutical substances/compositions |
Country Status (1)
| Country | Link |
|---|---|
| GB (2) | GB8410636D0 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1988004293A1 (en) * | 1986-12-02 | 1988-06-16 | Malcolm Francis Graham Stevens | Antifolate agents |
| JPH03502033A (en) * | 1987-11-27 | 1991-05-09 | ブリテツシユ・テレコミユニケイシヨンズ・パブリツク・リミテツド・カンパニー | optical communication network |
| WO2000043373A2 (en) * | 1999-01-22 | 2000-07-27 | Amgen Inc. | Kinase inhibitors |
| WO2001007027A2 (en) * | 1999-07-22 | 2001-02-01 | Vertex Pharmaceuticals Incorporated | Pyrimidine derivatives for the treatment of viral diseases |
| US6495558B1 (en) | 1999-01-22 | 2002-12-17 | Amgen Inc. | Kinase inhibitors |
| US7371758B2 (en) * | 2003-03-13 | 2008-05-13 | National Science & Technology Development Agency | Antimalarial pyrimidine derivatives and methods of making and using them |
-
1984
- 1984-04-26 GB GB848410636A patent/GB8410636D0/en active Pending
-
1985
- 1985-04-26 GB GB08510664A patent/GB2158068A/en not_active Withdrawn
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1988004293A1 (en) * | 1986-12-02 | 1988-06-16 | Malcolm Francis Graham Stevens | Antifolate agents |
| US4992444A (en) * | 1986-12-02 | 1991-02-12 | Stevens Malcolm F G | Antifolate agents |
| JPH03502033A (en) * | 1987-11-27 | 1991-05-09 | ブリテツシユ・テレコミユニケイシヨンズ・パブリツク・リミテツド・カンパニー | optical communication network |
| WO2000043373A2 (en) * | 1999-01-22 | 2000-07-27 | Amgen Inc. | Kinase inhibitors |
| WO2000043373A3 (en) * | 1999-01-22 | 2000-12-28 | Kinetix Pharmaceuticals Inc | Kinase inhibitors |
| US6495558B1 (en) | 1999-01-22 | 2002-12-17 | Amgen Inc. | Kinase inhibitors |
| WO2001007027A2 (en) * | 1999-07-22 | 2001-02-01 | Vertex Pharmaceuticals Incorporated | Pyrimidine derivatives for the treatment of viral diseases |
| WO2001007027A3 (en) * | 1999-07-22 | 2001-08-09 | Vertex Pharma | Pyrimidine derivatives for the treatment of viral diseases |
| US7371758B2 (en) * | 2003-03-13 | 2008-05-13 | National Science & Technology Development Agency | Antimalarial pyrimidine derivatives and methods of making and using them |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8510664D0 (en) | 1985-06-05 |
| GB8410636D0 (en) | 1984-05-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |