AU612788B2 - Process for the preparation of thiophene derivatives and also new dihydrothiophene 1-oxides - Google Patents

Abstract

Thiophene derivatives with an optionally substituted amino group on the thiophene ring are prepared by dehydrogenation of dihydrothiophenes which are substituted in the same manner as the desired thiophene derivatives, using H2O2, the dihydrothiophenes being reacted in a first reaction step with H2O2 in neutral medium to give the corresponding sulphoxides, and, in the second reaction step, these are then rearranged with acid to give the thiophene derivatives. The dihydrothiophene-1-oxides which are formed in this process as intermediates are novel compounds. They, and equally the thiophene derivatives obtained from them by rearrangement with acid, are intermediates mainly in the crop protection agent sector and pharmaceutical sector.

Description

I i l~ili~U J Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

612788 Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority .Related Art: Int. Class .Naie of Applicant: Address of Applicant:

.I

HOECHST AKTIENGESELLSCHAFT 45 Bruningstrasse, D-6230 Frankfurt/Main Republic of Germany 80, Federal Actual Inventor: ROBERT RIPPEL, HANS-WOLFRAM FLEMMING and MANFRED RUKWIED Address for Service EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the invention entitled: PROCESS FOR THE PREPARATION OF THIOPHENE DERIVATIVES AND ALSO NEW DIHYDROTHIOPHENE 1-OXIDES The following statement is a full description of this invention, including the best method of performing it known to us

I

1 HOECHST AKTIENGESELLSCHAFT HOE 88/F 037 Dr. Me/rh Description Process for the preparation of thiophene derivatives and also new dihydrothiophene 1-oxides It is known that thiophene derivatives can be prepared by dehydrrgenating dihydrothiophenes, examples of the dehydrogenating agents used being chlorides and bromides of sulfuric or phosphoric acid, chlorine, bromine, N-halogen compounds, tetrachloroquinone (chloranil), nitrosobenzene, iodosobenzene, selenium or sulfur. Hydrogen peroxide H 2 0 2 has also already been described as a dehydrogenating agent 10 for specific cases; cf., for example, A.P. Stoll and R.

S: Suess, Helvetica Chimica Acta volume 57, Fasc. 8 (1974) No. 269-270, pp. 2487-2492. In this literature reference 4-ethoxycarbonyl-3-hydroxy-2-phenyldihydrothiophene is dehydrogenated with H 2 0 2 in ethanolic solution at 15 60-65 C to give the corresponding thiophene derivative; the reaction takes place in accordance with the following equation: C20C 0 H5C2OOC OH I H 202 CCH5 2 S 6 5 S06 5 The yield for this reaction is quoted as 90 Other dihydrothiophenes namely those carrying, as substituents, electron-donating groups, such as, for example, the amino group or a substituted amino group do not afford the corresponding thiophene derivatives with H 2 0 2 in glacial acetic acid,' but instead the dihydrothiophene sulfones; cf. T. Takaya et al., Bull. Chem. Soc. Japan, volume 41, pp. 2086-2095 (1968). An example particularly described in this literature reference is the reaction of 3 -ethoxycarbonylamino-4-ethoxycarbonyl-2,5-dihydrothiophene I I k 2 with H 2 0 2 /gLacial acetic acid:

H

5

C

2 00C ,NHCOOC2H 5 +2H202 CHCOOH LJ^2°2 H5C C

NHCOCH

°2 sulfone 0

S.

S

5

*SSS

*S S 0 It has now been found that it is also possible to dehydrogenate those dihydrothiophenes which carry the amino group or a substituted amino group as substituents by means of

H

2 0 2 to give the corresponding thiophene derivatives, if the dehydrogenation is carried out in two stages, name- 15 Ly first reacting the dihydrothiophenes with H 2 0 2 in a neutral medium, in the course of which the dihydrothiophene S)oxides are formed, and then adding an acid to the dihydrothiophene 1-oxides with or without isolation of the Latter in the course of which the rearrangement 20 to give the corresponding thiophene derivatives takes place.

oS* o S S 5 S S

S

*5 5 0 0 elo oo oo The invention therefore relates to a process for the preparation of thiophene derivatives of the formula I 3 4/ R I II

",N

11 7C 1s R in which R 1

R

5 independently of one another denote hydrogen or organic radicals by dehydrogenating dihydrothiophenes of the formulae IIa and/or Iib C 2~\ I i H H I S R 3 in which the radicals R R 5 have the same meaning as in formula I, which comprises carrying out the dehydrogenation by means of H 2 0 2 and in 2 stages, a) by reacting the dihydrothiophenes of the formulae IIa and/or IIb with an at least approximately equimolar amount of H 2 0 2 in a neutral solvent or diluent in the absence of acid(s), in the course of which the 1oxides of the initial dihydrothiophenes are formed, and b) by adding an acid to the dihydrothiophene 1-oxides formed in stage with or without the isolation of S the latter, in the course of which the dihydrothiophene 1-oxides undergo rearrangement to give the thiophene derivatives of the formula I.

In terms of formulae the process can be represented as follows: 3 R H3 SN 4_ 1 R N

/R

RR 54- CN R C R H 0 IIa fIIa 4 -R 3 4 /R 3 C C/N N 2 C 5 R I R RCS R

C-R

H I H H 0 L IIIb 3 4 N he R CC C 2 H1 R/NR II II R 'S 1 4 The invention also relates to the two individual process stages a) and b) and to the dihydrothiophene 1-oxides (of the formulae IIIa/IIIb) formed in stage a).

It could not have been expected and is, therefore, extremely surprising that the reaction of T. Takaya et al.

(loc. cit.) starting from dihydrothiophenes substituted by amino groups and from H 2 0 2 can be guided by the modification according to the invention into a completely different direction namely to the formation of the corresponding thiophene derivatives (instead of the dihydrothiophene sulfones). The decisive factor for this different course is quite evidently that no acid is present at the start of the reaction.

The process affords high yields and purities of the products and is extremely non-harmful in terms of the environment and waste disposal. Hitherto it has only been possible to convert dihydrothiophenes substituted by amino groups into :20 the corresponding thiophene derivatives using dehydrogenating agents which are less harmless in terms of the environment and waste disposal; the ability also to carry out this conversion by means of H 2 0 2 from which no byproducts other than water are formed constitutes an outstanding advantage and advance.

The substituents R to R in the abovementioned formulae I, IIa/IIb and IIIa/IIIb can independently of one another be H or organic radicals.

Organic radicals preferred for R R and R are optionally substituted aliphatic radicals, cycloaliphatic and araliphatic radicals, optionally substituted aromatic radicals, alkoxycarbonyl, carboxamido, acyl radicals or CN; preferred organic radicals for R 2 and R are optionally substituted aliphatic radicals, cycloaliphatic and araliphatic radicals, optionally substituted aromatic radicals and acyl radicals; in addition one of the two radicals R 2 or R can also denote alkoxycarbonyl, or i 5 R and R 3 together with the N atom to which they are attached, can also form a 5-membered to 7-membered ring which can also contain another heteroatom of the type 0, S or N as a ring member and can also be substituted.

The following organic radicals are particularly preferred for R 1 to R 5 R R 4 and R C 1

-C

4 -alkyl,

C

5

-C

6 -cycloalkyl, CH 2

-C

6

H

5

C

6

H

5

COOCH

3

COOC

2

H

5

CONH

2

COCH

3

COC

2

H

5 or CN; R and R 3

C

1

-C

4 -alkyl, optionally substituted by

COOCH

3 or COOC 2

H

5 C5-C6-cycloalkyL, (CH 2 1 3

-C

6

H

5

C

6

H

5 optionally substituted by OH, OCH 3

OC

2

H

5

F,

CL or Br, or CO(C1-C5-alkyl) in which the alkyL radical 15 can be substituted by OH, F, CL, Br, (C 1

-C

4 )-akkoxy,

NH

2 or (Ci-Cg)-alkyLamino groups, and one of the radicals 2 3 R or R can, in addition, also be COOCH 3 or COOC 2

H

5 *2 3 or R and R 3 together with the N atom to which they are attached, can form a pyrrolidino, piperidino, morpho- 20 lino, piperazino or homopiperazino ring.

The starting dihydrothiophenes of the formulae IIa and lib S* are either known from the literature or can be prepared analogously to known processes. Known processes are, for example, quoted in the abovementioned literature reference of T. Takaya et al. (loc. cit.) cf. especially page 2090 and in DE-C 1,643,325. A summarizing recent survey is contained in the book by Weissberger, The Chemistry of Heterocyclic Compounds, A Series of Monographs, Arnold Weissberger and Edward C. Taylor, volume 44/part 21 "Thiophene and Its Derivatives", edited by S. Gronowitz (1986).

The starting dihydrothiophenes are reacted in stage a) of the process according to the invention with an at least approximately equimolar amount preferably with an approximately 1-molar to 2-molar amount of H 2 0 2 in a neutral solvent or diluent and in the absence of acid(s).

Suitable neutral soLvents or diluents are water and/or neutral organic solvents. The following may be mentioned as examples of neutral organic solvents: alcohols, such as, for example, methanol, ethanol, 1propanol, isopropanol, 1-butanol, 2-butanol, tert.-butanoL or 2-methyipropanol; aliphatic and cycLoaliphatic hydrocarbons, such as, for example, pentane, 2-methylbutane, hexane, 2,2-dimethylbutane, 2,3-dimethybutane, 2-methylpentane, 3-methylpentane, heptane, cyclohexane, methylcycLohexane, 1,2- *..dimethylcyclohexane, 1,3-dimethylcyclohexane or 1,4dimethylcyclohexane; 15 aromatic hydrocarbons, such as, for example, toluene, xylenes or isopropylbenzene; aliphatic and aromatic halogenated hydrocarbons, such as, for example, tetrachloroethyene, 1,1,2,2-tetrachloroethane, 20 1,1,1,2-tetrachloroethane, methylenechloride, dichloropropane, carbon tetrachloride, 1,1,2-trichloro-1,2,2-trifluoroethane, trichlorofluoromethane, 1,2-dichoroethane, 1,1-dichloroethane or chlorobenzene; ethers, such as, for example, diethyl ether, di-n-butyl ether, diisopropyl ether, diisoaryl ether, methyl tert.butyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane or anisole; esters, such as, for example, methyl acetate, ethyl acetate or butyl acetate; acid amides, such as, for example, dimethylformamide or dimethylacetamide.

Solvents or diluents which are particuLarly preferred are water and C 1

-C

4 -akanos (in particular ethanol and isopropanol), on their own or mixed with one another.

The reaction temperature in stage a) can vary within a fairly wide range. In general, the reaction temperature here is between about -20 and about +100 0 C, preferably between about -15 and about +70 0

C.

In order to carry out the reaction, the appropriate dihydrothiophenes of the formulae IIa and/or IIb are first dissolved or suspended in an appropriate neutral solvent or diluent. The corresponding amount of H 2 0 2 preferably also mixed with one or more of the solvents or diluents mentioned above is then added dropwise in a normal manner and the mixture is kept at the reaction temperature until starting material can no longer be detected; the detection is carried out in a customary 15 manner, preferably by taking a sample and carrying out a .thin layer chromatogram.

The dihydrothiophene 1-oxides of the formulae Ilia or IIIb formed can be isolated either by cooling and filtering off 20 with suction or by concentrating the solution. They can in S"some cases be formed as mixtures of diastereomers, and these can be separated by chromatography. The dihydrothiophene 1-oxides of the formulae IIla and IIIb are new compounds.

In the course of the rearrangement according to stage b) of the process according to the invention the dihydrothiophene 1-oxides of the formulae Ila and IIIb afford the equivalent thiophene derivatives. For this rearrangement it is possible to redissolve or resuspend the dihydrothiophene 1-oxides which have been isolated in one of the abovementioned solvents or diluents, or the reaction mixture obtained in stage a) can be processed further directly as such.

An acid is added dropwise or introduced in the form of gas (HCL or HBr) into the solution or suspension. Depending on the starting compounds, catalytic or larger amounts of acid are preferable or necessary for this.

8 The acids used can be inorganic and/or organic acids.

Aqueous, alcoholic or ethereal solutions of hydrogen chloride or hydrogen bromide or sulfuric acid are preferred.

The reaction temperature possible embraces the range between the solidification point and the boiling point of the solvent or diluent used; room temperature is preferred for this reaction.

The mixture is worked up in a customary manner. The free aminothiophenes can be obtained in a known manner from the aminothiophene salts formed in a given case.

The new dihydrothiophene 1-oxides and also the known thio- 15 phene derivatives formed by the rearrangement thereof in accordance with the process of the invention are valuable starting materials or intermediates for the preparation of, in particular, plant protection agents and pharmaceuticals. Examples of pharmaceuticals which may be 20 mentioned here are the substituted 3-aminoacylaminothiophenes of the general formula IV below, which are described in DE-C 1,643,325 mentioned above and which are suitable, above all, as local anesthetics:

R

R3 NH-C-A-N II (IV) Wf.: X 0 R" R S R 1' 2 in which R is H or an organic radical, R is an organic radical or R and R2' can aso together with the N atom to which they are attached form a ring, 3' 5' R R are H or organic radicals and A is a CI-C4alkylene group.

The compounds are prepared, for example, in accordance with variant b) of the process of the DE-C text, as follows: 9 R NH2 R R 3-CO-A-N/

R

4 5 HOOC-A-N/ R R 2 R R S R 5 (VI) (IV) The starting materials can be prepared more advantageously and in a manner less harmful to the environment than hitherto by the process according to the invention via the new intermediates IIIa/IIIb.

S.

15 The following examples serve to illustrate the invention without, however, limiting the latter. The melting points and decomposition points quoted are not corrected and depend on mixtures of diastereomers which may be formed.

S 20 Example 1

S.

a) 3-Amino-4-methoxycarbonyl-2,5-dihydrothiophene 1-oxide 0 3.2 g (0.02 mol) of 3-amino-4-methoxycarbonyl-2,5-dihydrothiophene are suspended in 30 ml of isopropanol. 2.2 ml

S.

of 35 strength hydrogen peroxide are added, with cooling. The mixture is then stirred at an internal temperature of 50 0 C until starting material can no longer be detected in a thin layer chromatogram (approx. 5 hours).

The mixture is then cooled in an ice bath and the precipitated crystals are filtered off with suction and washed with ice-cold isopropanol and with diethyl ether. Yield: g (91 of theory). When recrystallized from methanol, the crystals melt at 137 1400C.

A number of other dihydrothiophene 1-oxides were prepared analogously; the details can be seen from Table 1.

I I 10 TabLe 1 0 No. R 1 R2 R' R' R M.p1. (00C) la lb 0eg lh S lo 1 C C 0*0 1k V *5 IsC

H

COOCH 3

H

H

COOCH 3

H

H

COOCH 3 COOCH 3 C000H 3

H

H

CH 3 COCH 3

H

H

H

-(OH 2) 2C6 H5 -COCH 3 -COOC

H

-COOC H 4

-C

-C

6

OH

OH 3 OH 3

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

H

COO00

H

3 OH 3

ON

COOCP,

3 CH 3 -0000H 3 -0000H 3 OH 3 OH 3 OH 3

ON

ON

000CM 3 OH 3

ON

OH 3 OH 3 OH 3 137-140 212-218 165-167 oi L 93- 98 119- 122 oi L 13 2-13 158-165 oi l oi L 88- 93 13 1-138 17 1-17 oi L 93- 98 oi L H 000H 3 COOCH O H 2-0000c H5 COOCH O H 2- OOH3

OH

1 3 0000113 OC-OH-NHC3 H7 H oi L 11 Example 2 3-Amino-4-methoxycarbonylthiophene 3.8 g (0.02 mol) of 3-amino-4-methoxycarbonyL-2,5-dihydrothiophene 1-oxide are suspended in 20 mL of isopropanoL.

ml of a 5 N solution of hydrogen chloride in isopropanoL are added dropwise, with ice cooling, and the mixture is then stirred for approx. 1 hour at a bath temperature of 60 0 C. When the thin Layer chromatogram indicates complete reaction, the suspension is evaporated to dryness on a rotary evaporator, and the residue is triturated with a Little ethyl acetate and the product is filtered off with suction and dried. Yield: 2.8 g (89 of theory); 15 melting point 194-2010C) The thiophene derivatives in Table 2 were prepared analogously.

20 Table 2 3 252 S12 3 5 S No. R R R R R m.p.(C) S2a H H H COOCH 3 H 194-201 (HC1) 2b COOCH 3 H H CH 3 H 128-131 3 3 (HCl) 2c H H H CN H 214-216 (HC1) 2d H -(CH 2 3

C

6

H

5 H COOCH H 145-148 (HC1) I I 12 Table 2 (continued) 1 2 3 4 5 No. R R R R R oC) 2e COOCH COCH H CH H 117 3 3 3 2f H COCH H COOCH H 58- 2g H -COOC2NH H COOCH H 49- 52 2h COOCH -COOC2H5 H CH 3 H 80- 83 2i COOCH -C 4-4-0CH H CH3 H 97-100 2k COOCH3 CH H CH H 151-154 (HC1) 21 H C H5 CH3 CN H 52- 53 2m H CH 3 CH CN H 142-144 (HC1) 2n CH H H COOCH H 154-159 3 3 15 (HC1) 20 COCH H H CH H 161-162 .3 3 (H1) 2p H -COCH 3 H CN H 162-167 2q COOCH -CH2COOC2H5 H CH3 H 48- 2 00H 3 2 2 5 OH3 20 2r COOCH -CH2- COOCH3 CH H 72- 74 0 CH 2s COOCH OC-CH-NHC H H CH H 175-176 3 37 3 (HC1) ExampLe 3 3-Amino-2-methoxycarbonyL-4-methyLthiophene 3.46 g (0.02 mol) of 3-amino-2-carbomethoxy-4-methyL-4,5dihydrothiophene are dissolved in 25 mL of isopropanol, and 2.2 mL of 35 strength hydrogen peroxide are added dropwise, with ice cooLing. Stirring is continued for minutes at room temperature. The mixture is then cooled with ice water and 4 ml of 5 N hydrochloric acid in isopropanol are added. The mixture is then heated to 0 C and is stirred at this temperature for approx. minutes. It is worked up by distilling off the isopropanoL, stirring the crystalline residue thoroughly in a little ethyL acetate and filtering off the product with suction 13 and drying it.

YieLd of hydrochloride: 3.86 g 93 of theory), melting point 128-130 0

C.

Melting point of free base: 85 0

C.

The compounds described in ExampLe 2 can also be prepared analogously in a one-pot process.

C.

C C

S.

C

C..

a.

S. 0 e.g.

CC

0C S 04 S S S

C.,

S

C

S.

C

C.

SC S S S

C.

CS

S C

S

.55,55

C

t

L

Claims (8)

1. A process for the preparation of a thiophene deriv- ative of the formula I 3 2 II II R 2 1 1 5 in which R to R independently of one another denote :I H or organic radicals by dehydrogenating a dihydrothiophene of the formulae IIa and/or IIb N NN I I R I* a R 4 3 i in which the radicals R1 to R 5 have the same meaning as in formula I, which comprises carrying out the de- j hydrogenation by means of H 2 0 2 and in two stages, a) by reacting a dihydrothiophene of the formulae IIa S*and/or IIb with an at Least approximately equimolar amount of H 2 0 2 in a neutral solvent or diluent in the absence of acid(s), in the course of which the 1-oxide of the initial dihydrothiophene is formed, and b) by adding an acid to the dihydrothiophene 1-oxide formed in stage with or without isolation of the latter, in the course of which the dihydrothiophene 1-oxide undergoes rearrangement into the thiophene derivative of the formula I.

2. A process for the preparation of a dihydrothiophene H 3 SI II I R H 0 IIIa R4C /N R2 H 0 IIIb in which R to R 5 independently of one another denote H or organic radicals, wherein a dihydrothiophene of the formulae IIa or IIb a a a.t a a.. a, a. a a a. a. sa a. a. a a. S t *i a, a *c a 66 a a. a a /R 3 R -C R IS C c\ 2 I I R R- C, /C -R H H IIa lib in which R1 to R have the same meaning as in the formulae IIIa and IIIb is reacted with an at least ap- proximately equimolar amount of H 2 0 2 in a neutral solvent or diluent in the absence of acid(s).

3. The process for the preparation of a thiophene deriv- ative of the formula I as claimed in the definition in claim 1, wherein an acid is added to a dihydrothiophene 1-oxide of the formulae IIIa and/or IIIb H 3 I /R R4 C /N R 2 R I II H 0 R H O 4 R 3 RR /N R2 H 0 IIIh IIla 16 1 5 in which R to R independently of one another denote H or organic radicals, in the course of which the dihydro- thiophene 1-oxide undergoes rearrangement to give a thio- phene derivative of the formula I.

4. The process as claimed in one or more of claims 1-3, 1 5 wherein the radicaLs R to R in the formulae I, IIa, IIb, IIIa and IIIb have the following meaning: 1 45 R R and R independently of one another H, optionally substituted aliphatic radicals, cycloaliphatic and araliphatic radicals, optionally substituted aromatic radicals, alkoxycarbonyl, carboxamido, acyl radicals or bass as CN; *Pa 2 3 R and R 3 independently of one another H, optionally 94 *a substituted aliphatic radicals, cycloaliphatic and arali- phatic radicals, optionally substituted aromatic radicals and acy radicals; and, in addition, one of the two radi- 2 3 2 cats R or R can also denote alkoxycarbonyl, or R and R together with the N atom to which they are at- tached, can also form a 5-membered to 7-membered ring which can also contain another heteroatom of the type 0, S or N as a ring member and can also be substituted. .9 The process as claimed in one or more of claims 1 4, 1 5 wherein the radicals R to R in the formulae I, IIa, "IIb, IIIa and IIIb have the following meaning: *-R 1 R 4 and R 5 independently of one another H, C1-C 4 -aky, C

5 -C 6 -cycoalkyL, CH 2 -C 6 H 5 C 6 H 5 COOCH 3 COOC 2 H 5 CONH 2 COCH 3 COC 2 H or CN; R2 and R3: independently of one another H, C 1 -C 4 alkyl, optionally substituted by COOCH 3 or COOC 2 H 5 C 5 -C 6 -cycoaky, (CH 2 )1- 3 -C 6 H 5 C 6 H 5 optionally substituted by OH, OCH 3 OC 2 H 5 F, CL or Br, or CO(C 1 -C 5 -aky) in which the aLky radical can be substituted by OH, F, CL, Br, (C 1 -C 4 )-akoxy, NH 2 or (C 1 -C 8 )-aLkyamino groups, and one of the radicals R 2 or R3 can, in addition, also be COOCH 3 or COOC 2 H 5 or R 2 and R3, together with the N atom to which they or R and R together with the N atom to which they 1 I; are attached, for a pyrrolidino, piperidino, morphgolino, piperazine or homopiperazino ring.

6. The process as claimed in one or more of claims 1 to 5, wherein the reaction is carried out in water or a neutral organic solvent, preferably in water and/or a C -C 4 o* alkanol, as a solvent or diluent.

7. A dihydrothiophene 1-oxide of the formlae IIIa and II I b: H 3 3 /R R 1C 1 1R R RS C, R 5 C-- H 0 H 0 IIIa IIIb in which R R and R s denote alkyl substituted or unsubstituted aliphatic radicals, alkyl substituted and unsubstituted cycloaliphatic and araliphatic radicals, alkyl substituted and unsubstituited aromatic radicals, alkoxycarbonyl, carboxamido, acyl radicals or CN; and R' and R independently of one another denote H or aliphatic radicals substituted by COOCH 3 or COOC 2 Hs, cycloaliphatic araliphatic and aromatic radicals substituted by OH, OCH 3 OC 2 H 5 F, Cl or Br or acyl radicals substituted by OH, F, Cl, Br, (C1 4 )-alkoxy, NH, or (C 1 _)-alkylamino groups, and in addition one of the two radicals R 2 or R 3 can also denote alkoxycarbonyl, or R 2 and R 3 together with the N atom to which they are attached can also form a 5-7 membered ring which can also contain another heteroatom of the type 0, S or N as a ring member and can be substituted. Melb Disk 10/1.43 MG -18

8. A dihydrothiophene 1-oxide as claimed in claim '7, in which the radicals R 1 to R 5 have the meaning indicated in claim DATED this 9th day of April, 1991. 0 0 S. @0 000 0000 0* *6 S S* 00 S *e 0 0* 00 HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT ATTORNEYS 2ND FLOOR "THE ATRIUM", 290 BURWOOD ROAD, HAWTHORN, VIC. 3122. AUSTRALIA *0550@ 0 0550 5 5 @0 0 0 So Meib Disk 10/1.43 MG