AU658148B2 - Use of radioactive metal ion complexes with all-cis-1,3,5-triamino-2,4,6-cyclohexantriol and their derivates for x-ray diagnosis and in tumor therapy as well asfor producing x-ray diagnostic and tumor therapy agents - Google Patents

Description

OPI DATE 30/03/92 APPLN. ID 84367 91 INTE AOJP DATE 14/05/92 PCT NUMBER PCT/EP91f0167q BER DIE

(PCT)

(51) Internationale Pateatklassiikation 5 (11) Internationale Veriiffentlichungsnummer:. NYO 92/04056 A61K 49/02, 43/00 Al (43) Internationales Veriiffentlicliungsdatum: 19. Milrz 1992 (19.03.92) (21) Internationales Aktenzeichen: PCT/EP9I/01679 (74) Anwalt: HRABAL, Ulrich; Tfirk Glle Hrabal, Brucknerstr. 20, D-4000 Dfisseldorf 13 (DE).

(22) Internationales Anmeldedatum: September 1991 (05.09.91) (81) Restimmungsstaaten: AT (europJisches Patent), AU, BE (europilisches Patent), CA, CH (europilisches Patent), Prioritfitsdaten: DE (europiiisches Patent), DK (europiiisches Patent), ES P 40 28 139.6 5. September 1990 (05.09.90) DE (europadisches Patent), FR (europfiisches Patent), GB (europliisches Patent), GR (europiiisches Patent), IT (europilisches Patent), JP, KR, LU (europiiisches Patent), (71) Anmelder (fAir alle Bestimnungsstaaten ausser US): LABO- NL (europ~isches Patent), SE (europ1~isches Patent), US.

RATORIEN HAUSMANN AG [CH/CH]; Rechenstrasse 37, CH-9001 St. Gallen (CH).

Veriiffentlicht (72) Erfinder; und Mit internationalem Recherchenberich.

Erfinder/Anmelder (nur ffir US) ERNI, Isidor (CH/CH]; Eidgen6ssische Technische Hochschule Z~rich ETH- Zentrum, Universitatsstr. 6, CH-8092 Ziirich (CH).

SCHNEIDER, Walter [CH/CH]; HEGGETSCHWEI- LER, Hans, Kaspar WCHICH); Eidgeno1ssische Technische Hochschule Zfirich ETH-Zentrum, Universit~sstr. 6, CH-8092 Zfirich GEISS ER, Peter [CH/CH]; Marweesstr. 8, CH-9014 St. Gallen (CH).

(54) Title: USE OF RADIOACTIVE METAL ION COMPLEXES WITH all-cis- 1,3,5-TRIAMINO-2,4,6-CYCLOHEXAN4- TRIOL AND THEIR DERIVATES FOR X-RAY DIAGNOSIS AND IN TUMOR THERAPY AS WELL AS FOR PRODUCING X-RAY DIAGNOSTIC AND TUMOR THERAPY AGENTS (54) Bezeichnung: VERWENDUNG DER KOMPLEXE RADIOAKTIVER METALLIONEN MIT all-cis-1,3,5-TRIAMINO- 2,4,6-CYCLOHEXANTRIOL UND SEINEN DERIVATEN FOR RONTGENDIAGNOSTISCHE ZWEK- KE UND IN DER TUMORTHERAPIE SOWIE ZUR HERSTELLUNG VON MITTELN FOR RONT- GENDIAGNOSTISCHE ZWECKE UND FOR DIE TUMORTHERAPIE (57) Abstract The use is disclosed of radioactive metal ion complexes with all-cis- 1,3,5-triamino-2,4,6-trihydroxy-cyclohexane, their deniyates, salts or quaternary ammonium salts for X-ray diagnosis and in tumor therapy, as well as for producing X-ray diagnostic and tumor therapy agents.

(57) Zusanimenfassung Verwendung der Komplexe radioaktiver Metallionen mit all-cis-1,3,5-Triamino-2,4,6-trihydroxy-cyclohexan, semnen Derivaten, Salzen oder quatemniren Ammoniumsalzen ffir r6ntgendiagnostische Zwecke und in der Tumortherapie sowie zur Herstellung von Mittein f~r r~ntgendiagnostische Zwecke und ftir die Tumortherapie.

Use of complexes of radioactive metal ions with all-cis- 1,3,5-triamino-2,4,6-cyclohexanetriol and its derivatives for radiodiagnostic purposes and in tumour therapy and for the preparation of agents for radiodiagnostic purposes and for tumour therapy.

The invention relates to the use of complexes of all-cis-l,3,5-triamino-2,4,6-cyclohexanetriol and its derivatives with ions of radioactive metal isotopes for radiodiagnostic purposes and in tumour therapy and for the preparation of agents for radiodiagnostic purposes and for tumour therapy.

The use of metal complexes for therapeutic or diagnostic administration is described in Inorganic Chemistry in Biology and Medicine, ACS Symposium Series 140, American Chemical Society, Washington, D.C. (1980), pages 91 to 101, 103 to 119 and 121 to 140. Complexes of radioactive isotopes have also been employed for pharmaceutical purposes, in particular for diagnostic purposes.

They can be used for the demonstration of various organs of the body. A disadvantage of the demonstration methods to date is the limited possibility of employment for certain applications. For example, radiographic demonstration of the human and animal heart has not been possible.

The object of the invention is to provide novel possibilities for radiodiagnostic demonstration and for tumour treatment.

It has emerged that this object can be achieved by using complexes of radioactive metals, in particular radioactive metal cations with 2,4,6-trihydroxycyclohexane [sic] and its derivatives for radiodiagnostic purposes and in tumour therapy or for the preparation of agents for radiodiagnostic purposes and for tumour therapy.

The complexes used according to the invention are preferably based on radioactive metal isotopes which are a, 3 or y emitters. Examples of radioactive isotopes which can be used are those of technetium, iron, gallium, ruthenium, indium, dysprosium, samarium, tullium [sic], 2 yterbium [sic] and yttrium. Specific examples are ions of the following isotopes: 5'Fe, 6Cu, 6Ga, "6Ga, 72Ga, 9sRu, 97Ru, "rTc, 9"Rh, 'In, 1In, Dy, Sm, Tm, 19Yb, 182 Re and 8 Re.

The ligands used for the complexes according to the invention are all-cis-1,3,5-triamino-2,4,6cyclohexanetriol and its derivatives as described, for example, in European Patent 0 190 676 (US Patent 4 794 197) and in Helv. Chim. Acta. Vol 73, 1990, pages 97 to 105. They are prepared by the methods indicated therein.

Particularly suitable ligands are all-cis- 1,3,5-triamino-2,4,6-trihydroxycyclohexane or its derivatives of the general formula (I) HO R

RI

4 4

V

1 in which the symbols R 1

R

2

R

3

R

4

R

5 or R. are identical or different and represent hydrogen atoms, alkyl groups or -CO-alkyl groups, where the alkyl in the alkyl or -COalkyl groups has 1 to 18 carbon atoms, and where the alkyl and -CO-alkyl groups can each, independently of one another, contain one or more, identical or different functional groups, and their salts with inorganic or organic pharmacologically customary acids or their quaternary ammonium salts of the general formula (II), (IIa) or (IIb) HO OH HO -5 OH O .OH HOH X -H lio 3h 3 with pharmaceutically utilisable anions, in which R I to R 6 and R 7

R

8 and Rg denote, independently of one another, the unsubstituted or substituted alkyl groups or -COalkyl groups defined above, or all-cis-1,3,5-triamino- 2,4,6-trihydroxycyclohexane derivatives of the general formula 'F'7~-f7 Q\H/ 14 1V o \4

T

0{HO^L~ o E? n 4 8 in which the substituents on the nitrogen atoms are, independently of one another, H or CH 3 and are preferably all CH 3 Examples for the radicals R, to R 6 in the ligands are alkyl or -CO-alkyl groups which can contain one or more, identical or different functional groups. In each case a maximum of one symbol of the symbols R 1 to R 9 on each nitrogen atom is preferably a secondary or tertiary alkyl substituent or a -CO-alkyl group. Moreover, the other symbols preferably represent hydrogen or methyl.

A preferred group of ligands are those in which all the radicals R, to R 6 and R z to R 9 are methyl or -COCH 3 groups.

The alkyl groups or -CO-alkyl groups of the substituents R 1 to R 8 and R, to R 9 preferably have one or more functional groups which can coordinate to metal cations.

Examples of functional groups on the alkyl groups or -COalkyl groups are -OH, -COOH or salts thereof, -CONH 2 -CON(OH)R, where R represents an alkyl group with 1 to 6, in particular with 1 to 4 carbon atoms, -OPO 3

H

2 and salts thereof, -P0 3

H

2 or salts thereof, -SR (in which R has the above meaning), and the esters of the above acids, -CN, 4- 0' and/or and/or their salts.

Preferred examples are those of the ligands of the formula (ha) or (hIb) in which one or more or all of the sym~bols R, to R. have, independently of one another, the following meaning: a) -H f) ,CON (OH) R R=alkyl with Cl 1 2 b) -alkyl, with 1-12 C preferably C 1 -4 atoms or -CO-alkyl with 1-12 C atoms in the g) (CH 2 nOPO302 alkyl h) (CH 2 nPO23 c) (CH 2

),OH

d) (CH 2

).~CO

2 R=alkyl with Cl 1 2 1 preferably

C

1 4 e) (CH 2

),CONH

2 5 1Y 0 -(Cqz) n 1) (CH m)

US-

where n is 1, 2 or 3, and the salts thereof; and those in which one or more or all of the symbols Ri to R, have, independently of one another, the following meaning: a) -CO-(CH 2

OH

b) -CO-(CH 2 ),CO2c) -CO-(CHz)nCONHa d) -CO-(CH 2 )nCON(OH)R R=alkyl with Cl 12 1, preferably C 1 -4 e) -CO-(CH 2 )nOPO h) -co n- -0-C i) -o -(CO j) k) f) -CO-(CH 2 ).PO-3 g) -CO-(CH 2 )nSR R=alkyl with C,_ 2 z, preferably Ci-4 where n is 1, 2 or 3, and the salts thereof.

A particularly preferred group of ligands are those of the formula (IIa) and ((IIb) in which at least one of the radicals R, to R, and, in particular, in each case the radicals R 1

R

3 and R 5 represent the group -(CH 2 )n-COOH in which n has the meaning of 1 to 3 and particularly preferably of 2. The remaining substituents R 2

R

4 R. and R 7 to R 9 are preferably hydrogen 6 or CH 3 and these remaining substituents are preferably identical. Compounds of this type of the formula are particularly well suited for tumour therapy.

A particularly important group of ligands of the complexes used according to the invention are those which have positive charges so that the complexes prepared therefrom are positively charged. Complexes of this type are, for example, particularly suitable for radiodiagnostic purposes, in particular for the radiodiagnostic demonstration of the heart of warmblooded species (human -nd animal). The positive charges can derive either from the quaternary nitrogen atoms of the compounds of the formula (IIa), (IIb) and (IV) or from substituents with positively charged functional groups which can be located on the ligands of the formula or (III) but also on the ligands of the formulae (IIa), (IIb) and The positive charges can be obtained, for example, by protonation or by quaternisation of nitrogen atoms which are present.

Particularly favourable examples are compounds of the formulae (IIa), (IIb) and (IV) in which all the substituents (in the formulae (IIa), (IIb) the substituent groups R, to represent methyl groups.

Examples of substituents with positively charged functional groups are alkyl groups with quaternary ammonium groups, such as trimethylamino groups or triethylamino groups, for example those of the formula

-(CH

2 )n-NR 3 in which n denotes 1 to 3 and, in particular, 2 and R represents alkyl with 1 to 4 carbon atoms, in particular methyl.

Particularly preferred compounds of the formula are those in which R, R 3

R

5

-CH

2

CH

2 COOH and R 2 R4 R, H; and those in which R, R3 R 5

-CH

2

CH

2

N(CH

3 3 and R 2

R

4 Rr H.

The complexes used according to the invention are easily prepared from aqueous solutions or suspensions of salts, hydroxides or oxides of the radioactive metals of interest in each case, and aqueous solutions or 7 suspensions of the ligands. The aqueous solutions can, for example, be acidic. The amounts generally used for this purpose are such that 2 mole of ligands of the formula (IIa), (IIb) or 1 mole of the formula (III) or (IV) are present per 1 mole of metal ions. A small excess of the ligand is preferably used.

To prepare technetium complexes it is possible, for example, to start from technetium hexafluoride or technetium hexachloride solutions which can be initially reduced so that technetium (IV) ions are present, after which an aqueous solution with excess ligand is then added.

A portion of the radioactive metals or metal cations in the complexes employed according to the invention can be replaced by corresponding non-radioactive isotopes. For example, the complexes can be in the form of mixtures of complexes of radioactive metals or metal cations with non-radioactive metals or metal cations. Moreover, the non-radioactive metals or metal cations and the radioactive metals or metal cations can be identical or different. For example, in the case where radioactive iron isotopes are used they can be present together with non-radioactive iron. It is possible in the preparation of products of this type, for example, to form the complex from a solution of iron(III) ions in the presence of radioactive iron(III) ions.

The complexes used according to the invention can be prepared by the manufacturer or supplier; however, they are often also prepared in situ in the x-ray laboratory or treatment laboratory from the prepared solutions.

The resulting aqueous solutions of the complexes can be employed for radiodiagnostic purposes and for tumour therapy. Specific applications are x-ray tomography, positron emmission [sic] tomography and, in particular, demonstration of the human and animal heart, with positively charged complexes preferably being employed for this purpose. It is particularly favourable 8 for diagnostic purposes to choose complexes which are 7 or p+ emitters; a emitters are preferably employed for controlling tumours, for example for controlling cancer.

The complexes used according to the invention are employed in the form of aqueous solutions; they can be administered in a variety of ways, in particular by intravenous administration.

Example 1: Synthesis of all-cis-1,3,5-tris(2'-aminopropionic acid)- 2,4,6-cyclohexanetriol [sic] 1 mn1 (0.324 g) of 2,4,6-cyclohe.ianetriol sulphate was dissolved in a little water and loaded onto an ion exchanger column (Dowex 1, X 4, 50/100 mesh, OH form). It was eluted with water until the eluate had a neutral reaction. The basic fractions were concentrated in a rotary evaporator. This solution of 1 mmol of triaminocyclohexanetriol was mixed with 3 mmol (3 ml of 1M aqueous solution) of acrylonitrile and left to stand in the dark under nitrogen for one week. The intermediate product all-cis-1,3,5-tris(2'aminopropionitrile)-2,4,6-cyclohexanetriol [sic] was obtained by evaporation in a rotary evaporator 1 H NMR (90 MHz, D 2 0, pD 2.97 ppm 3.49 ppm 3.60 ppm 4.54 ppm (m,3H).

13 C NMR (62.9 MHz, D 2 0, pD 14.9 ppm, 40.6 ppm, 57.0 pm, 63.2 ppm, 117.4 ppm.

pK values (approximate); 3.0, 4.5, 6.3.

The nitrile was hydrolysed by boiling in concentrated hydrochloric acid under reflux for 6 hours. The all-cis-l,3,5-tris(2'-ammoniopropionic acid)-2,4,6-cyclohexanetriol [sic] trichloride was obtained by evaporation in a rot r evaporator.

1. -Tas taken up in a little water and neutralised to about pH 4.5 with potassium hydroxide solution.

I

9 The all-cis-l,3,5-tris(2'-aminopropionic acid)-2,4,6cyclohexanetriol [sic] precipitated during this. The product was filtered off, dissolved in dilute acid (pH 3) and again precipitated by neutralisation, filtered off and finally dried under high vacuum.

Element microanalysis: Formula of the substance: C 15

H

27

N

3 0 9 MW: 393.39 C H N calculated 45.80 6.92 10.68 found 41.50 7.24 9.31 These values are consistent with 2.8 mole of water of crystallisation per mole of product.

1H NMR (200 MHz, D 2 0, acid): 2.95 ppm 3.53 ppm 3.72 ppm 4.72 ppm (m,3H).

13C NMR (200 MHZ [sic], DzO, acid): 32.8 ppm, 43.5 ppm, 59.6 ppm, 66.1 ppm, 176.9 ppm.

pK values (approximate): 6.2, 8.2, 9.7.

Example 2: Synthesis of 59 ferri all-cis-l,3,5-tris(2'-aminopropionic acid)-2,4,6-cyclohexanetriol [sic] 1 mmol of all-cis-1,3,5-tris(2'-aminopropionic acid)-2,4,6-cyclohexanetriol [sic] (from Example 1) was dissolved in about 20 ml of 0.1 M hydrochloric acid.

1 mmol of Fe(III) (1 ml of 1M FeCl 3 with 2 mCi of 59 FeC1 3 (Amersham) in HCI IM) was added. KOH (about 1 M) was slowly added to the clear yellowish solution, which became darker yellow during this. The product began to precipitate out at about pH 3. Alkali was then added until the pH was about The precipitated 59 ferri all-cis-1,,3,5-tris- (2'-aminopropionic acid)-2,4,6-cyclohexanetriol [sic] was 10 filtered off on a G4 sintered disc and subsequently purified by dissolving in 0.1 M HC1 and precipitating at pH 4.5. The product was finally dried under high vacuum.

Structural identity with the non-radioactive [sic] labelled product was established on the basis of spectroscopic properties.

Analysis of the non-radioactively labelled complex leads to the conclusion that the formula is CisHz 4

N

3 OgFe.

Example 3: Synthesis of all-cis-l,3,5-trihydroxycyclohexane-2,4,6tri-N-acetylamide [sic] 3.28 g (18.5 mmol) of the amine (from Example 1) were dissolved in 100 ml of methanol, and 35 ml (370 mmol) of acetic anhydride were added. The mixture was stirred at room temperature overnight. Methanol and excess acetic anhydride were removed in vacuo. The resulting product was recrystallised from ethanol and dried over phosphorus pentoxide under high vacuum for 24 h. Yield 86 melting point 300"C.

Element microanalysis: Formula of the substance: C 15

H

21

N

3 0 6 MW: 303.3 C H N calculated 47.52 6.98 13.85 found 46.21 6.82 13.61 1H NMR (200 MHz; D 2 0) 2.05 ppm 3.97-4.04 (q;2H) 13C NMR (200 MHz, D 2 0) 176.4 ppm; 72.8 ppm; 53.5 ppm, 24.7 ppm Solubility: readily soluble in water 11 Example 4: Synthesis of 59 ferri hexane-2,4,6-tri-N-acetylamide [sic] 1 mmol of al-cis-1,3,5-trihydroxycyclohexane- 2,4,6-tri-N-acetylamide [sic] was dissolved in about ml of 0.1 M hydrochloric acid. 0.5 mmol of Fe(III) ml of 1M FeCl 3 in HCI 1M) with 2mCi of 59 FeC1 3 (Amersham) was added.

Then exactly the calculated amount of KOH (IM) [lacuna] the hydrochloric acid and a further 8 equivalents of alkali per Fe were added all at once (pH Back-neutralisation with HCl(1M) until the pH is [sic] in the region 5.0 0.2 ip [sic] subsequently carried out, checking with a pH meter. The uncharged iron complex with the composition Fe(H 3

L

2 (L ligand) precipitates [sic]. The complex is soluble in a buffer with physioligical [sic] pH and above that.

Structural identity with the non-radioactively labelled product was established on the basis of spectroscopic properties.

Analysis of the non-radioactively labelled complex leads to the conclusion that the formula is FeC 24

H

39

N

6 Oi 8H 2 0.

Example Synthesis of gadolinium all-cis-1,3,5-tris(2'-aminopropionic acid)-2,4,6-cyclohexanetriol [sic] 1 mmol of all-cis-l,3,5-tris(2'-aminopropionic acid)-2,4,6-cyclohexanetriol [sic] from (Example 1) was dissolved in about 8 ml of 1 mol/l hydrochloric acid.

1 mmol of GdCl 3 (100 mg of GdC 3 1 x 6H 2 0/ml of HC1 1 mol/1) was added. The pH of the clear colourless solution was slowly adjusted to 4.5 with NaOH (about 2 mol/1). This resulted in initial turbidity at pH 3 and precipitation at pH 4.5. The precipitated gadolinium all-cis-1,3,5tris -aminopropionic acid) -2,4,6-cyclohexanetriol [sic] was filtered on a G4 sintered disc and subsequently washed with distilled water. The product was finally 12 dried under high vacuum at 40 0

C.

Element microanalysis: Formula of the substance:

C

calculated found calculated*

H

2 0) 32.90% 22.13% 22. 03%

C

15

H

24 N3OqGd H N 4.42% 7.67% 6.58% 5.17% 6.65% 5.14% 14W: 547.62 Gd 28.72% 19 19.23% These values are consistent with 15 mole of water of crystallisation per mole of product.

Claims (3)

1. A method of radiodiagnostic demonstration comprising the step of administering to a patient a complex of radioactive metal ions with all-cis-1,3,5- triamino-2,4,6-trihydroxycyclohexane or its derivatives of the general formula (I) HO \OH Ho N R6 RR4. N (I) R4-' N R2 as ligands, in which the symbols R 1 R 2 R, R 4 R 5 or R 6 are identical or different and represent hydrogen atoms, alkyl groups or -CO-alkyl groups, where the alkyl in the alkyl or -CO-alkyl groups has 1 to 18 carbons atoms, and where the alkyl and -CO-alkyl groups can each, independently of one another, contain one or more, identical or different functional groups, and their salts with inorganic or organic pharmacologically customary acids or their quaternary ammonium salts of the i general formula (IIa) or (IIb) R 9 R9 R5 HO OH HO OH HO \OH SR8. IHO R6 HO N R6 R8 HO N -R6 R4/ N R7 /R1 R4"7 N R- R3 1 RS R 1 R2 R2 R2 II IIa IIb with pharmaceutically utilisable anions, in which R, to R 6 and R 7 Rs and R 9 denote, 15 independently of one another, the unsubstituted or substituted alkyl groups or -CO- alkyl groups defined above, or with all-cis-1,3,5-tri-amino-2,4,6- trihydroxycyclohexane derivatives of the general formula BMII:SM:#10688.CL 3 Fcbuay 1995

14- SN NHO OH HO OH III N H or n=4-8 N /7 N( (CH2)n n=4-8 C. C. ,I CCC. in which the substituents on the nitrogen atoms are, independently of one another, H or CH 3 as ligands, and subjecting said patient to x-ray or other radio imaging procedures. 2. A method according to claim 1, wherein the radioactive metal ions are a, B or y emitters. 3. A method according to claim 1 or claim 2, wherein the radioactive metal ions are ions of radioactive isotopes of iron, copper, gallium, yttrium, ruthenium, technetium, rhodium, indium, dysprosium, samarium, thulium, ytterbium or rhenium. 4. A method according to any one of claims 1 to 3, wherein the complex is positively charged. 5. A method according to claim 4, wherein the ligand is selected from the group 15 consisting of the formulae (IIa), (IIb) or (IV) according to claim 1. 6. A method according to claim 5, wherein the radicals R, to R 9 in the formulae (IIa) and (IIb) are each methyl groups and that the substituents on the nitrogen atoms on the formula (IV) are methyl groups. BMII:SM:#10688.CL 3 Fcbmary 1995 15 7. A method according to claim 5, wherein the radicals R 1 to R 6 in the formulae (IIa) and (IIb) are methyl groups and the radicals Rg and R are each H. 8. A method according to any one of claims 1 to 4 wherein the alkyl groups or -CO-alkyl groups contain one or more functional groups which can coordinate to metal ions. 9. A method according to claim 4, wherein, in the ligands of general formula (I) at least one of the radicals R 1 R 3 and Rs has the general formula (CH 2 No (R) 3 in which n 1, 2 or 3, in particular 2, R is alkyl with 1, 2, 3 or 4 carbon atoms, and the radicals R 2 R 4 and R 6 are hydrogen atoms or alkyl groups with 1 to 18 carbon atoms. A method according to any icue of claims 1 to 3, wherein the ligand is selected from the group consisting of general formula (IIa) or (IIb) and in which the radicals R 1 R 3 and R 5 are alkyl groups which have functional groups and 15 the general formula (CH)n COOH, in which n 1, 2 or 3 and, in particular 2 and the radicals R 4 and R 6 to R 9 are each H. 11. A method according to any one of claims 1 to 10 wherein the complex is administered in admixture with a pharmaceutically acceptable diluent or carrier. 12. A method according to any one of the preceding claims wherein the complex is administered intravenously. BMII:SM:#10688.CL 3 Febmary 1995

16- 13. A method according to claim 12 wherein the radiodiagnostic demonstration is directed towards the heart of the patient. 14. A method of therapeutically treating a tumour comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a complex of radioactive metal ions with all-cis-1,3,5-triamino-2,4,6- trihydroxycyclohexane or its derivatives of the general formula (I) HO OH HO N R6 N /tI "R 1 R2 as ligands, in which the symbols R 1 R 2 R 3 R 4 R 5 or R 6 are identical or different and represent hydrogen atoms, alkyl groups or -CO-alkyl groups, where the alkyl in the alkyl or -CO-alkyl groups has 1 to 18 carbons atoms, and where the alkyl and -CO-alkyl groups can each, independently of one another, contain one or more, identical or different functional groups, and their salts with inorganic or organic pharmacologically customary acids or their quaternary ammonium salts of the S general formula (IIa) or (IIb) a.as R9 R5 R5 HO VOH HO OH H R8 HO R6 HO RR6 H N 7 7 R4- N RN NR4 R N R2 R2 R2 II Ia IIb with pharmaceutically utilisable anions, in which R, to R 6 and R 7 R 8 and R 9 denote, independently of one another, the unsubstituted or substituted alkyl groups or -CO- BMI:SM:#10688.CL, 3 Fbnruary 1995 17 alkyl groups defined above, or with all-cis-1,3,5-tri-amino-2,4,6- trihydroxycyclohexane derivatives of the general formula N N OH N T HO \OH' (CH2)n IV n=4-8 n=4-8 in which the substituents on the nitrogen atoms are, independently of one another, H or CH 3 as ligands. DATED: 3 February 1995 CARTER SMITH BEADLE Patent Attorneys for the Applicant: LABORATORIEN HAUSMANN AG S S S S S. 55 S S S 5555 o S S S. S. S S S S 5 S S S S S IIMI[SM:N10688.CL3 b1ny99 3 Febrawy 1995 Abstract: Use of complexes of radioactive metal ions with all-cis-1,3,5-triamino-2,4,6-trihydroxycyclohexane, its derivatives, salts or quaternary ammonium salts for radiodiagnostic purposes and in tumour therapy, and for the preparation of agents for radiodiagnostic purposes and for tumour therapy. INTERNATIONAL SEARCH REPORT International Application No PCT/EP 91/01679 I. CLASSIFICATION OF SUBJECT MATTER (if several classification svmbols ncPiv. indicate ll) According to International Patent Classification (IPC) or to both National Classification and IPC Int.C1. 5 A 61 K 49/02, 43/00 II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System I Classification Symbols Int.Cl. 5 A 61 K Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included In the Fields Searched Ill. DOCUMENTS CONSIDERED TO BE RELEVANT' Category I Citation of Document, t1 with indiction, where appropriate, of the relevant passages 12 Relevant to Claim No.13 X EP, A1, 0190676 3 August 1986, (LABORATORIEN HAUSMANN AG) see claims 21-24 WO, Al, 9008138 (NYCOMED AS ET AL.) 26 July 1990, see pages 18-19 and the claims WO, Al, 9110454 (BYK .DEN LOMBERG CHEMISCHE FABRIK GMBH) 25 July 1991, see the claims 1-15 1-15 1-15 Special categor cited documents: 10 document deft g the general state of the art which Is not considered to be of particular relevance earlier document but published on or after the international filing date document which may throw doubts on priority claim(s) or which is cited to establish the publication date of another citation or other special reason (as specified) document referring to an oral disclosure, use, exhibition or other means document published prior to the international filing date but later than the priority date claimed later document published after the International filing date or priority date and not In conflict with the application but cited to understand the principle or theory underlying the Invention document cf particular relevance; the claimed invention cannot be considered novel or cannot be considered to involve an inventive step document of particular relevance; the claimed Invention cannot be considered to involve an inventive step when the document Is combined with one or more other such docu- rrents, such combination being obvious to a person skilled in the art. document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Malling of this International Search Report December 1991 (05.12.91) 20 December 1991 (20.12.91) International Searching Authority Signature of Authorized Officer EUROPEAN PATENT OFFICE Form PCT/ISA/210 (second sheet) (January 1985) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO.PCT/EP 91/01679 SA 50727 This annex lists the patent ramily members relating to the patent documents cited In the above-mantioned intarnallonai search report. The members are as contained in the European Patent Office EDP file on 31/10/91 The European Patent office Is in no way liable for theSep32rticulars which are merely given for the Purpiose of Information. Patent document PbiaonPatent family Publication c i e rc re o tP bII inecreot date member(*) dat EP-Al- 0190676 13/08/86 AU-B- DE-A-C- JP-A- US-A- 589156 3503614 61210058 4794197 05/10/89 07/08/86 18/09/86 27/12/88 WO-Al- 9008138 26/07/90 AU-D- EP-A- 4957390 04,52392 13/08/90 23/10/91 WO-Al- 9110454 25/07/91 NONE For more details about this annex see official Journal of the European patent Office, No. 121,'2 EPO FORM P0470 INTERNATIONALER RECHERCHENBERIGHT SI nternationaies Aktenzeichen PCT/EP 91/01679 1. KLASSIFIKATION DES ANMELDUNGSGENSTANDS (boi mehrnren Klass iitwtlonssym boien sind 2110 anzupeben) 6 Nach der Internationalen Patontklasslfikatlon (IPC) odor nach der nationalen Kiasssifikatlin und der IPC int.Ct.' A 61 K 49/02, 43/00 11. RECHERCHIERTE SACHGESIMF Recherctiierter Mindestpr~fstoff 7 Klaisitikationssyster Klassifikatlonssymbolo InI.CL. 5 A 61 K Recherctiierte nicht zumn Mlndestprufstaft gehdrende Verd'!entlichungen, saweit dies,4 unter die recherchiurten Sachgebiete fattenil Ill. EINSCHLAGIGE VEROFFENTUCHUNGEN' Art Kerinzeichnung der VerbIfontiichungli,saweit erforderlich unter Angabe der mafigebtichen Teiie 1 2 Bair. Anspi-uch Hr 1 X EP, Al, 0190676 (LABORATORIEN HAUSMANN AG) 1-15 13 August 1986, Siehe AnsprUche 21-24 A WO, Al, 9008138 (NYCOMED AS ET AL.) 1-15 26 Juli 1990, Siehe Seiten 18-19 und die AnsprUche P,X WO, Al, 9110454 (BYK GULDEN LOM~BERG CHEMISCHE 1-15 FABRIK GMBH) 25 Juli 1991, Siehe die Anspri~che BeAoVere Kateug, ie den silgeibnen Stand dertlichngenk IT Spitere Vertilfentlichung, die nach dam internationalen An- dA erlntla icht dibe sr bden lgmie tsam dnershn meidedatum odor dam PrioriIiitsda turn verdffentllcht warden deliler, aer nchlalsbesndembedut~m anuzaen st 1st und mit der Anmeldung nicht kattidlort, sondern nur zum -EI aliens Dakument, das jodoach ersat am odor lnch dam inferno- Verstindnis des der Erfindung zugnindeliegenden Prinzips tionalen Anmeidedatum veaffentlicht warden 1st Wanr den ihr zugnundeliegenden Theorie angegeben Ist 'L Vertiffentichung, die gemignot 1st, elnen Pnrtitsa nspruch IX Verdffentlichung von besanderor Bedoutung, die beanspruch- zweifeihaft erscheinen zu lassen, odor durch die dax Verdi- to Erfindung kana nicht als neu odor out erfinderischer Tit1g- fentlchungsdstum elnhr anderen im Recherchenbericht go- knit beruhend betrscbtol warden nannten Veriilfenttichung belegt: warden soil odor die aus emn- em andoren beonderen Grund angeguben ist (wi. ausgefllhnt) Vardffentlichung van besanderar Bedeutung, die boanspruch- 'O Verblfenttichung. die sich aul em.e mdndliche Otebaug, i Erfindung kann nicht sis auf erfinderischer Titigiceit be- Offebarng, ruhend betrachtet werden, wenn die Verdffentllchsing mit elno Bei'. zurlg, ewne Aussfliung odor andere Mafinahmen omnen oder mebreren anderan Verbffontlichungen dieser Kate- bezieht gonie in Verbindung gebracht wird und dies. Verbindung (On IF" Verdifferltichung, die var dem internationaten Anmeldeds- einen Fachmann nahetlegend lot. turn, abor nach dom beanspruchten Prlorititsdatum verbffent- Veriflfentlichung, die Mlgilnd dersetben Patentfsmniii st lcht warden ist IV. BESCHEINIGUNG Datum des Abschtusses der intennstianalen Recherche Absendedatum des internstionaten Recherchenberichts Dezember 1991 I20. 12. 91 In te na t i on le R e c h e n c h e n b e h rd e U n te n s c h rift d e s b e v o lm c h itlg e n B d i e e n Eunapilsches Patentamnt I Formblatt PCT/ISAI21O (Blatt 2) (Januan 1985) ANHANG ZUM INTERNATIONALEN RECHERCHEN BERICHT OBER DIE INTERNATIONALE PATENTANMELDUNG NR.PCT/EP 91/01679 SA 50727 In diesn Anhang sind die Milgileder dur Patentfamillen der Imn obengenannten internationalmn Rechurchenbericht aingalflhrien Patenidokumento angegeon. a~/09 Die Angabon Obher die Familianmilgilider antspmechen dam Stand der Datel des Europiiiachen Patentamis a~/09 Diese Angabmn dienen nur zur Untarrnchtung und erfolgen ohne Gawihr. Im Recherchenbericht Datum der Mlitgiled(ar) der Datum der angefiihrtes Patentdokument Verbltentlichung Patentiamilia VerIiifentlichung EP-Al- 0190676 13/08/86 AU-B3- 589156 05/10/89 DE-A-C- 3503614 07/08/86 JP-A- 61210058 18/09/86 US-A- 4794197 27/12/88 WO-Al- 9008138 26/07/90 AU-0- 4957390 13/08/90 EP-A- 0452392 23/10/91 WO-Al- 9110454 25/07/91 KEINE Far nihere Elnzetheiten zu diesem Anhang sishe Amisbialt des Eumopilschun Patentsmts, Nr.12/82 EPO FORM P0473