NZ206018A

NZ206018A - Platinum-diamine complexes and compositions for treating cancer

Info

Publication number: NZ206018A
Application number: NZ206018A
Authority: NZ
Inventors: F Verbeek; J Berg; E J Bulten
Original assignee: Tno
Priority date: 1982-10-21
Filing date: 1983-10-20
Publication date: 1986-02-21
Also published as: GB2128615B; FR2534907A1; IE832459L; DK483083A; IT8323359A0; CH658244A5; CS775283A2; SE8305783D0; NO833825L; DK75592D0; YU43554B; IE56124B1; ES526670A0; IT1169858B; NO171276B; NL8204067A; ATA373083A; CS242888B2; AU2027583A; FI76351C

Description

<div class="application article clearfix" id="description"> 2 06019 Priority Date(s): *?■). Complete Specification Filed: $Q7 Class: c£>7tg&tJas>. .«?.£>. I .13.. .... ^C5,sioo--.co7^rjV.«r?. " ' 2l FEB 19$ Publication Date: P;0. Journal, No: NEW ZEALAND Patents Act 1953 N. Z.No. COMPLETE SPECIFICATION "Platinum-diamine complexes, a process for the preparation thereof, a process for the preparation of a medical composition using a such platinum-diamine complex for the treatment of cancer, as well as the thus shaped composition." We, NEDERLANDSE CENTRALE ORGANISATIE VOOR TOEGEPAST- NATUURWETEN- SCHAPPELIJK ONDERZOEK; incorporated under the laws of The Netherlands of Juliana van Stolberglaan 148, 2595 CL THE HAGUE, The Netherlands, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement : - - 1 - (Followed by 1A.) 20 CO18 - lA - Platinum-diamine complexes, a process for the preparation thereof, a process for the preparation of a medical composition using a such platinum-diamine complex for the treatment of cancer, as well as the thus shaped composition. The invention relates to novel platinum-diamine complexes, and to a pharmaceutical composition using such a platinum-diamine complex for the treatment of cancer, for example, malignant swellings and malignant tumors, as well 5 as to a shaped composition obtained by using this process. Such platinum-diamine complexes are known from the article by A.P. Zipp and S.G. Zipp, J.Chem.Ed., 54 (12), (1977), page 739, which describes the application of cis-platinum diamine dichloride (PDD) for the treatment of cancer. 20 It is mentioned that the platinum compounds have a broad spectrum of activity as antitumor agents, but also that they have serious drawbacks, in particular that they are toxic to the kidneys. As method for counteracting the kidney toxicity a cis-platinum diamine dichloride is often 25 used in combination with another substance or administered with large quantities of liquid or other techniques are used to bring about an adequate flow-through of the kidneys. A number of other platinum amine complexes are known including compounds having the formula 2 of the formula 20 sheet. Wadley Medical Bulletin, Vol. 7, No. 1, pp. 114-134, discloses a large number of platinum diamine complexes, including cis-platinum diamine dichloride, for the treatment of cancer. Here, too, the kidney toxicity is stated as the 25 most important drawback of these compounds. Chem. and Eng. Neu/s, 6th June 1977, pp. 29-30, also describes cis-platinum diamine chloride and its application for the treatment of cancer. Kidney toxicity is also mentioned as the most important drawback of these compounds. 2 206018 In an article in Cancer Chemotherapy Reports Part I, Vol. 59, No. 3, May/June 1975, pp. 629-641, the kidney toxicity of cis-platinum-II-diamine dichloride is also reported. Because of the toxicity of PDD to the kidney and its lou/ therapeutic index, other platinum complexes for the treatment of cancer have been sought. For this purpose combinations of cis-platinum diamine-II-dichloride with other chemothe rapeutic agents u/ere tested; novel platinum complexes were also tried, but they u/ere found to be toxic. It was found, for instance, that although cis-dichloro-biscyclopentyl amine platinum(II) is only slightly toxic to the kidneys, it is toxic to the spleen. So-called "platinum blues", a mixture of different amounts of five or more inseparable components have also been disclosed for the treatment of cancer. United States Patent Kos .3,892,790; 3,907,663 and 4,119,653 disclose a large number of platinum diamine complexes, including the compound having formula 2 of the formula sheet. In all of these compounds with a nucleus, nitrogen atoms are linked directly to the nucleus. The compounds of the first two United States patents were compared with cis-platinum diamine dichloride and were found to have better effects. None of the patents ■< , states anything about kidney toxicity. In New Zealand Patent Specification No 195926 platinum diamine complexes are described, which are characterized by the formula 1 of the formula sheet, wherein R^ and R2 are independently of each other a hydrogen atom or a substituted or unsubstituted alkyl, cycloalkyl, aryl or aralkyl group,! while R^ and R2 may be together a substituted or unsubsti-tuted cycloalkyl group, R^ and R^ independently of each other are a hydrogen atom or a substituted or unsubstituted alkyl, aryl or aralkyl group, and X is an anionic group. Now novel platinum diamine complexes have been found fE Ail Tt which are characterized by the formula 1 of the formuja^ ff shee t, whe re i n |/v R^ and R2 are both an ethyl group or together with 2 D£C|98§ 3 2.06018 carbon atom, to which, they are bonded, a cyclohexyl group, R^ and are both a hydrogen atom and X is a malonate group, an ethyl malonate group, a hydroxy malonate group, a carboxy phthalate group, a bis-chloro acetate group, a cyclobutane-l,l-dicarboxylate group, a dinitrate group or an axalate group, or a sodium salt of one of these groups. The invention further relates to a process for the preparation of these compounds characterised in that platinum-(III-diamine complexes having the formula [ i 1 / \ C-H. 2 N /X \>/ wherein R ^ and R2 are both ethyl or together with the carbon atom, to which they are bonded, a cyclohexyl group, artd X is a malonate group, an ethylmalonate group, a hydroxymalonate group, a carboxyphthalate group, a bis-chloro acetate group, a cyclobutane-1,1-dicarboxylate group, a dinitrate group or an oxalate group or a sodium salt of these groups, are prepared by reacting a compound having the formula R. L NH, CI •Pt' h C -H o \\ p\985««[ .0/ wherein and R^ have the above meaning, with AgNO^ in solution, whereafter the obtained product is reacted with a compound having the general formula XH wherein X has the above meaning and that a possible acidic hydrogen atom, if desired, is converted in a manner known per se to a sodium salt. 4 20&019 The invention further relates to a process for the preparation of a medical carpositicn, wherein these carpounds are used as active substance, as well as to the so-obtained shaped medical carposition. v An extensive research program carried out by the National Cancer Institute, Bethesda, U.S.A., and the European Organization for Research on the Treatment of Cancer, Brussels, Belgium, has shown that the oonpounds according to this invention display a high therapeutic activity against cancer in contradiction to the platinum complexes known up to now and used in practice for the ccarbat of cancer, like the cis-platinum diamine dichloride (PDD), therein it also appeared that the oonpounds according to the invention show little or none kidney toxicity. As it appears from the therapeutical activity values, mentioned in table A, the novel carpounds show an important anti-tumor activity against a large nurrfoer of different types of tumors, such as P388 lymphocytic leukonia (PS), L-1210 lymphoid leukemia (IE), ependyiroblastoma and B16 melanocarcincma (Bl). The therapeutical activity of the relative novel compounds is higher than that of the cis-platinum diamine dichloride (PDD) which is used as experimental clinical chemotherapeuticum. A very serious drawback of the PDD used in practice, as well of all other platinum-II- complexes with anti-cancer activity and known up to now (with the exception of those, which are described in New Zealand Patent Specification No 195926) is as already mentioned the high toxicity of these ccrrpounds, of which the kidney toxicity is the most dangerous and in fact limiting for the dose, which can be used in practice. Surprisingly the carpounds according to the invention do not show detrimental side effects an the kidneys. This was demonstrated by means of histological research of rats after treatment of toxic doses of the carpounds described herein below, while in a similar research with PDD serious kidney damages were found. The new complexes also have no prejudicial influence on the activity of the kidneys. A generally recognized, significant method for the determination of kidney toxicity relates to the evaluation of the percentage urea nitrogen in the blood (blood urea nitrogen, BUN), also indicated as non-protein nitrogen (non protein nitrogen, NPN). It further appears that the carpounds according to the invention have no single influence on the urea-nitrogen contents in the blood. As well for doses corresponding with the ID, n amount as with the LD__ amount J-U Oil the urea-nitrogen contents in the blood are identical to the control values. The corpound PI®, on the contrary, gives at a LD^o <^ose after the indicated times already a four times increase of the urea-nitrogen contents, Vvhile this at a LD^q dose is increased with a factor of not less than 11. 206 01! 5 Table A Anti-cancerous activity in mice3 Compound mouse code'3 tumorC dose/injection mg/kg '-v —1 NO ^ o formula 4 06 . LE 36,00 246 LE/cis-PDD 24,00 >500 (3/6) formula 5 BDF LE 40,00 200 formula 6 BDF LE 6,00 207 formula 7 BDF LE 128 229 (1/6) LE/cis-PDD 64 144 formula 8 BDF LE 24 214 LE-cis-PDD 18 144 formula 9 BDF LE 128 V ON (4/6) LE/cis-PDD 96 150 formula 10 BDF LE 128 >643 (3/6) LE/cis-PDD 96 188 formula 11 BDF LE 8 229 formula 12 BDF LE 80 283 LE/cis-PDD 80 231 formula 13 BDF LE 30 217 LE/cis-PDD 15 188 formula 14 BDF LE 6 200 LE/cis-PDD 6 163 formula 15 BDF1 LE/cis-PDD 16 230 a: More detailed information concerning the testing procedure and 25 interpretation, vide Instruction 14, Screening data summary interpretation and outline of current screen, Maryland, 20014, 1977. b: 02 = mouse code B^^F^ (BDF^); 03 = mouse code C 57 BL/6; 06 = mouse code C^F^ (CDF^). c: PS = P 388 lymphocytic leukemia; LE = L 1210 Lymphoid leukemia; 30 EM = ependymoblastoma; melano-carcinoma. d: Period of survival is the ratio of survival times of the treated mice (T) to untreated mice (C); the therapeutic activity is significant at T/C * 125. LE/cis-PDD means resistant to cis-PDD. 206018 ... 6 The preparation of the above mentioned compounds is illustrated in the follou/ing examples. The compounds were prepared according to the method of S.C. Dhara: Indian J.Chem. 8^, 193 (1970). 5 Example I Cis-dichloro-1,1-di(aminonrtethy 1) cyclohexane platinum(II) having the formula 3 of the formula sheet. To a solution of 16 g K^PtCl^ in 160 ml of water a solution of 26.4 g KI in 20 ml of water were added and the 10 mixture was heated for 5 min. in a water bath. Hereupon 6.4 g 1,1-di(aminomethy1) cyclohexane were added and after the mixture had been stirred for 5 minutes, the precipitate was sucked and washed three times with hot water, twice with cold ethyl alcohol and twice with ether. 15 11.8 g of this formed diiodo derivative were added to a solution of 6.6 g AgNO^ in 48 ml water. After the mixture had been stirred for 10 minutes at 95-100°C, the Agl was filtered off and washed with water. To the clear filtrate 3.28 g KC1 were added and the mixture 20 was stirred for 12 min. at 95-100°C. After the mixture had been cooled, the precipitate was sucked and washed with water. Yield: 6.0 g. Analysis (percentage by weight): 25 Calculated: C: 23.53; H: 4.45; N: 6.87; PT: 47.80 Found: 23.32; 4.46; 6.86; 47.63. Example II Preparation of cis-l,l-di(aminomethyl)-cyclohexane hydroxy-malonate platinum(II) having the formula 4. jq 1.6 g of the dichloro derivative, prepared according to example I (formula 3) were added to a solution of 1.28 g AgNOj in 25 ml of water. After stirring the mixture during 1 hour at 40°C the AgCl was filtered off and washed with water. ■j5 To the clear filtrate a solution of 0.456 g hydroxy- malonic acid and 0.455 g K0H in 10 ml of water was added. 20601B After stirring during 2 hours at room temperature the precipitate was filtered off and dried. Yield: 77 weight %. Analysis (weight ?o)s 5 Calculated: C: 29.01; H: 4.43; N: 6.15; Pt: 42.84; 0: 17.58 Found: 28.77; 4.38; 6.18; 42.96; 17.54. Melting point = 248°C (decomposition). Example III Cis-4-carboxyphthalato-l,l-di(aminomethy 1)-cyclohex ane-10 platinum(11) having the formula 5. 1.2 g of the dichloro derivative prepared according to example I (formula 3), were added to a solution of 1 g AgNO-j in 25 ml of water. After stirring the mixture during 1 hour at 40°C the 15 AgCl was filtered off and washed with water. To the clear filtrate 0.63 g 1,2,4-tricarboxybenzene was added and the mixture was stirred during 2 hours at room temperature. The precipitate was sucked off and washed with water. 20 Yield: 0.8 g (45 weight %) Analysis (weight ?o) : Calculated: C: 36.24; H: 4.29; N: 4.97; Found: 36.42; 4.13; 4.77. Example IV 2 5 Cis-l,l-di(aminomethyl)-cyclohexane-bis(chloro acetate)-platinum(II), having the formula 6. 1.6 g of the dichloro derivative prepared according to example I (formula 3), were added to a solution of 1.28 g AgNO^ in 25 ml of water. 30 After stirring the mixture during 1 hour at 40°C the AgCl was filtered off and washed with water. To the clear filtrate a solution of 0.73 g monochloro acetic acid and 0,45 g K0H in 25 ml water was added and the mixture was stirred during 2 hours at room temperature. 35 The precipitate was sucked off and washed with water. Yield: 1.3 g (65 weight %). Analysis (weight %): 206018 Calculated: C: 27.49; H: 4.23; H: 5.34; Found: 27.43; 4.21; 5.55. Example \l Cis-l,l-di(anninomethyl)-cyclohexane-nialonate-platinum(II) 5 having the formula 15. r This compound has already been mentioned in New Zealand Patent Specification No 195926, but its preparation is important for the following's^aw^les. ' 1.6 g of the dichloro derivative prepared according to 10 example I (formula 3) were added to a solution of 1.28 g AgMOj in 25 ml water. After stirring the mixture during 1 hour at 40°C the AgCl vas filtered off and washed with water. To the clear filtrate a solution of 0.4 g malonic acid 15 and 0.455 g K0H in 10 ml water was added. After stirring during 2 hours at room temperature the precipitate was filtered off and dried. Yield: 1.0 g (59 weight ?o). Analysis (weight %): 20 Calculated: C: 30.07; H: 4.59; H: 6.38; Pt: 44.40; 0: 14.57: Found: 29.98; 4.54; 6.32; 44.32; 14.57, Example VI Cis-2.2-die thy1-1,3-d iaminopropane-2-ethylmalonate-platinum (II), having the formuta 7, was prepared according to the 25 method of example V. Yield: 65 weight %. Analysis (weight ?o): Calculated + 2 C: 29.33; H: 5.74; N: 5.70; Found: 29.23; 5.64; 5.71. 30 Example VII Cis-2,2-diethyl-1,3-diaminopropane-2-hydroxymaIonate-platinum(11), having the formula 8 was prepared according to the method of example V. Yield: 87 weight %. 35 Analysis (weight %): Calculated + 1/2 H 2 0 J C: 26.55; H: 4.68; N: 6.19;^ Found: 26.67; 4.56; 6 2 0 6 0 1 8 9 The sodium salt of this compound having the formula 13 was prepared according to example IX. Example VIII Cis-l,l-di(aminomethyl)cyclohexane-2-ethyI-malonate-5 p 1 a t i n u m (II) having the formula 10 was prepared according to the method of example V. Yield: 64 weight %. Analysis (weight %) : Calc. + 1.5 H20: C:31.57; H:5.5fl; N:5.67; 0:17.79; Pt:39.43; 10 Found: 31.36; 5.47; 5.69; 18.02; 39.58. Example IX Cis-2,2-diethyl-l,3-diaminopropane-2-hydroxymalonate-platinum(II)-sodium salt having the formula 13. 0.5 g of the hydroxymalonate derivative prepared accor-15 ding to example VII (formula 8) were suspended in 25 ml water. 1.105 ml 0.1 N NaOH were added and the mixture was stirred during 30 min. at room temperature. The clear solution was evaporated to dryness and the 20 remaining solid was dried. Yield: 0.4 g (72 weight %) Analysis (weight %) : Calculated + 2 H20: C;23.91; H: 4,61; N: 5.58; Found: 23.75; 4.44; 5.52. 25 Example X Cis-l,l-di(aminomethyl)cyclohexane-l,l-cyclobutanedicarboxy-late-platinum(II) having the formula 12. 2 g of the dichloro compound, prepared according to example I (formula 3) were added to a solution of 1.6 g 3Q AgNO^ in 25 ml water. After stirring the mixture during 1 hour at 40°C the AgCl was filtered off and washed with water. To the clear filtrate a solution of 0.677 g 1.1-cyclo-butane dicarboxylic acid and 0.547 g K0H in 10 ml water was 35 added. After 2 hours at room temperature and 1 hour at 0°C the white precipitate was filtered off and dried. 206018 10 Yield: 1.4 g (62 weight. %) . Analysis (weight %) : Calculated + H20: C: 33.80; H: 5.27; N: 5.63; Found: 33.98; 5.02 5.77. 5 Example XI Cis-2,2-diethyl-l,3-diaminopropane-Itl-cyclobutane dicarbo-xylate platinum(11) , having the formula 9, was prepared according to the method of example X. Yield: 64 weight ?o. 10 Analysis (weight %): Calculated + 2.5 H20: Cs 30.46; H: 5.70; N: 5.47; Pt: 38.07; Found: 30.40; 5.44; 5.37; 38.16. Example XII Cis-l,l-bis(aminomethyl)cyclohexane platinum(II)nitrate^), 15 having the formula 11. 4 g cis-dichlora-1,1-bis(aminomethy 1)cyclohexane plati-num(II) (0.0097 mole) were suspended in 30 ml distilled water. To this 3.1 g AgNO^ (0.0182 mole) were added and sub-20 sequently the mixture was heated during 1 hour at 40°C while light was excluded. The formed silverchloride was filtered off and washed with distilled water (10 ml). The clear filtrate was evaporated under reduced pressure. 25 Weight solid substance: 4.17 g (93.5 weight %). Melting point : explodes at about 240°C; decomposes slowly at temperatures below 240°C. Analysis (weight ?o) : calcul.: C:20.83; 1-1:3.93; N:12.14 30 found : 20.9 ; 4.1 ; 11.9 . ^H-NMR-spectrum in DMSO-d^ (Varian T60) with respect to TMS: CH9 (ring) ch2 (nh2) '2 ) NH 2 35 satellites 195Pt-1H ].37 ppm 2.30 ppm 5.67 ppm 5.20 ppm 6.18 pp m 58 HZ 20601S 11 Ex ample XIII Cis-l,l-bis(aminomethyl)cyclohexane platinum(II)oxalate having the formula 14. 4.1 g Cis-dichloro-1,1-bis(aminomethyl)cyclohexane 5 platinum(II) (0.01 mole) n/ere suspended in 30 ml distilled water. To this 3.2 g AgNO-j (0,019 mole) were added and subsequently the mixture was heated during 1 hour at 40°C while light was excluded. 10 The formed silver chloride was filtered off and washed with distilled water (50 ml). To the filtrate 2.02 g potassium oxalate (0.01 mole) were added, whereafter the mixture was stirred during 1 hour at room temperature. 15 Subsequently the formed solid was sucked off, washed with distilled water and dried. Weightdry : 3.7 g (87 weight %) Analysis (weight %) : calc.; + 1.5 H20: C:26.55; H:4.68; N:6.19; Pt:43.13; 0:19.45; 2 0 found: 26.6; 4.6; 6.2; 43.4; 19.2. *H-NMR-spectrum in DMSO-d ^ (Varian T60) with respect to TMS: CH2 (ring) ch2 (nh2) nh2 25 satellites 1.32 ppm 2.17 ppm 5.45 ppm 4.83 ppm 6.08 pplfl 76 Hz 30 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 12 206018 WHAT WE CLAIM IS:

1. PI a ti nudi- (11) -d iamine complexes, characterized by the formula 1 of the formula sheet, wherein Rj and R2 are both ethyl or together with the carbon atom, to which they are bonded, a cyclohexyl group, 5 R^ and R^ are both a hydrogen atom and X is a malonate group, an ethylma1onate group, a hydroxymalonate group, a carboxyphthalate group, a bischloro acetate group, a cyclobutane-1,1-dicarboxylate group, a dinitrate group or an 10 oxalate group or a sodium salt o f se groups.

2. Platinum diamine complex according to claim 1, characterized by the formula 4 of the formula sheet.

3. Platinum diamine complex according to claim 1, characterized by the formula 5 of the formula sheet. 15

4. Platinum diamine complex according to claim 1, characterized by the formula 6 of the formula sheet.

5. Platinum diamine complex according to claim 1, characterized by the formula 7 of the formula sheet.

6. Platinum diamine complex according to claim 1, 20 characterized by the formula 8 of the formula sheet.

7. Platinum diamine complex according to claim 1, characterized by the formula 9 of the formula sheet.

8. Platinum diamine complex according to claim 1, characterized by the formula 10 of the formula sheet. 25

9. Platinum diamine complex according to claim 1, characterized by the formula 11 of the formula sheet.

10. Platinum diamine complex according to claim 1, characterized by the formula 12 of the formula sheet.

11. Platinum diamine complex according to claim 1, 30 characterized by the formula 13 of the formula sheet.

12. Platinum diamine complex according to claim 1, characterized by the formula 14 of the formula sheet.

13. A process for the preparation of a medical composition for the treatment of cancer characterized in^^'^7^ 3 5 as platinum-(II)-diamine complex a compound having the formula 1, of the formula sheet wherein 13 2060.18 Rj_» ^2' ^3» ^4 anc* * have the meaning defined in claim 1, is used.

14. The process according to claim 13, characterized in that as platinum-(11)-diamine complex the compound having 5 the formula 4 of th£ -formula sheet is used.

15. The process according to claim 13, characterized in that as platinum-(11)-diamine complex the compound having the formula 5 of the formula sheet is used.

16. The process according to claim 13, characterized in 10 that as platinum-(II)-diamine complex the compound having the formula 6 of the formula sheet is used.

17. The process according to claim 13, characterized in that as platinum-(11)-diamine complex the compound having the formula 7 of the formula sheet is used. 15

18. The process according to claim 13, characterized in that as platinum-(II)-diamine complex the compound having the formula 8 of the formula sheet is used.

19. The process according to claim 13, characterized in that as platinum-(11)-diamine complex the compound having 20 the formula 9 of the formula sheet is used.

20. The process according to claim 13, characterized in that as platinum-(II)-diamine complex the compound having the formula 10 of the formula sheet is used.

21. The process according to claim 13, characterized in 25 that as platinum-(11)-diamine complex the compound having the formula 11 of the formula sheet is used.

22. The process according to claim 13, characterized in that as platinum-(11)-diamine complex the compound having the formula 12 of the formula sheet is used. 30

23. The process according to claim 13, characterized in that as platinum-(11)-diamine complex the compound having the formula 13 of the formula sheet is used.

24. The process according to claim 13, characterized-in that as platinum-(11)-diamine complex the compound having 35 the formula 14 of the formula sheet is used. jV\ J S 14 206018

25. A process for the preparation of pi atinum-( I I ) - diamine complexes, characterized in that p 1 atinum-( 11 )-diamine complexes having the formula H„ H? R, C- N /X \>/ / \ / \ R0 C N x 1 H„ H n where i n and R2 are both ethyl or together with the carbon atom, to which they are bonded, a cyclohexyl group, and X is a malonate group, an ethylmalonate group, a hydroxymalonate group, a carboxyphthalate group, a bis-chloro acetate group, a cyclobutane-1,1-dicarboxylate group, a dinitrate group or an oxalate group or a sodium salt of any one of these groups, are prepared by reacting a compound having the formula Ho R l (\n9 CI •Pt^" wherein R^ and R2 have the above meaning, with AgNQ^ in solution, whereafter the obtained product is reacted with a compound having the general formula XH wherein X has the above meaning and that a possible acidic hydrogen atom, if desired, is converted in a manner knot per se to a sodium salt. 206018 15

26. The process according to claim 25, characterized in that a compound having the formula 4 of the formula sheet is prepared.

27. The process according to claim 25, characterized in that a compound having the formula 5 of the formula sheet is prepared.

28. The process according to claim 25, characterized in that a compound having the formula 6 of the formula sheet is pre pared.

29 The process according to claim 25, characterized in that a compound having the formula 7 of the formula sheet is prepared.

30. The process according to claim 25, characterized in that a compound having the formula 8 of the formula sheet is prepared.

31. The process according to claim 25, characterized in that a compound having the formula 9 of the formula sheet is prepared.

32. The process according to claim that a compound having the formula 10 is prepared.

33. The process according to claim that a compound having the formula 11 is prepared.

34. The process according to claim that, a compound having the formula 12 is prepared.

35. The process according to claim that a compound having the formula 13 is prepared.

36. The process according to claim that a compound having the formula 14 is prepared. NEDERLANDSE CENTRALE OPGANISA3TE VOOR ' * TOEGEPAST - NATUU^ETTENSCHAPPELIJK ONDERZOEK " 'N By their Attorneys HENRY n x -^3 .i BY: t ,/ \ . ... 25, characterized in of the formula sheet 25, characterized in of the formula sheet 25, characterized in of the formula sheet 25, characterized in of the formula sheet 25, characterized in of the formula sheet </div>