JPH05502456A - Radioactive metal ions and all-cis-1,3,5-triamino-2,4,6-cyclohexanetriol and its derivatives for radiodiagnosis and tumor treatment and for the production of radiodiagnostic agents and tumor treatment agents Use of complexes with - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] A radiodiagnostic agent and a tumor therapeutic agent for radiodiagnostic use and tumor treatment radioactive metal ions and all-one cis for the production of 1. ．． 3.5-triami/-2, Use of complexes with 4,6-chlorohexanetriol and its derivatives The present invention is useful for radiodiagnosis and tumor treatment; for the production of these agents. , all-cis-1,3,5-t')amino-2,4,6-ene chlorohexane triode Use of complexes of metals and their derivatives with ions of radioactive metal isotopes.

Use of metal complexes for therapeutic or diagnostic administration; Inorganic Chemi stry j, n Biology and Medicine, AC3Sy mposium 5eries 140. Amerjcan Chemj,c al　5ocity.

Washington, D.C. (1980), pages 91 to 101.130t.

119 and 121 to 140). Also, radioactive isotopes Complexes of elements are traditionally used, especially for diagnostic preparations. they are the body It can be used for the display of various organs of the body. I can do it. The disadvantage of explicit methods to date is that they can only be used for applications consisting of The reason is that it is limited. e.g. radiography of the viscera (human and animal) Conventionally, it was possible to display by (Manakara tko).

The purpose of the invention is to provide new possibilities for radiodiagnostic display and tumor treatment. It's about doing.

This purpose is for radiodiagnosis and tumor treatment as well as for the production of these agents. radioactive metals, especially radioactive metal cations, and all-cis-1.3.5-triamine using a complex with nor-2,4,6-dolyhydroxycyclohexane and its derivatives. It has become clear that this can be achieved by using

The complexes used according to the invention are radioactive metals that are alpha, beta or gamma emitters. Preferably it is based on isotopes. An example of a radioactive isotope that can be used is Techne. Thiium 1. Iron, gallium, ruthenium, indium, subbrosium, samarium um, thulium, ytterbium and yttrium. Specific examples are as follows Isotopes of “Fe,” “Cu-,” “Ga,” “Ga-,” “Ga-,” 95Ru, “R u,, 9gllllTcsOQmRh, ■’In, “3Ins”7Dys + 5”Se, ”’Tm, ””Yb.

There are 1B2Re and 1'18Re ions.

Ligands used in the complexes of the invention are e.g. European Patent No. 01.9067 No. 6 (U.S. Pat. No. 4,794,197) and r! elv, Chin, Acta, Vol　73.　1990. All items listed on page S 97 to 105 Su1.3.5-1-riamino-2,4,6-cyclohexandriol and It is a derivative thereof. These are manufactured by the method indicated therein.

Particularly suitable ligands are of the general formula (I) [In the formula, the symbols R1, R2, R5, R4, R6 or i are the same or different; hydrogen atom, alkyl group or -CO-alkyl1& (wherein the alkyl or The alkyl in the 100-alkyl group has 1 to 18 carbon atoms, and the alkyl and 100-alkyl groups are each independently one or more of the same or an all-cis-1,3,5-tria having Mino-2,4,6-dolyhydroxycyclohexane or its derivatives, and salts thereof with organic or organic pharmacologically customary acids or pharmaceutically usable acids. Ion and general formula (■), (IIa) or (nb) Il (In the formula, the substituents on the nitrogen atom are independently H or cE13, preferably all cis-1,3,5-triamino-2,4, It is a 6-1-lyhydroxycyclohexane derivative.

Examples of groups R1 to R6 in the ligand include one or more identical or different functional groups. an alkyl or -CO-alkyl group which may contain a group. In each case, the The symbol R1-1 on each nitrogen atom? , at most one symbol is the second or A tertiary alkyl substituent or a 100-alkyl group is convenient. Furthermore, that Preferably, other symbols represent hydrogen or methyl.

A preferred group of ligands is one in which all of the groups R1-R8 and R0-R0 are methyl. or -COCR3 group.

The alkyl group or -C〇-alkyl group of substituents R1 to R8 and R3 to P is, Preferably, it has one or more functional groups capable of coordinating with metal cations. The Al Ligands with a kill group or - (wherein is 1.2 or 3) and their one or more or all of the salts and symbols R] to R9 are independently of the following: meaning: a) -Co-(CT12)non b) -CO-(CJ)nCOz- c) -CO-(C■z). C0NI(2d) -CO-(CT12)nCON (OR)RR=alkyl (C+~1, preferably C5~4)e) -CO-(C )lt)nOPO3''-f)-CO-(CFI2).Po,2-g)-Co -(CL). 5R R=alkyl (01-+2, preferably Cl-4)-〇2C (where n is 1.2 or 3) and its salts. I can do it.

Particularly preferred groups of ligands include formulas (I), (n), (Ila) and (n b) in which one or more of the groups R1 to R11, in particular in each case and groups R9, R8 and R5 are groups -(CH2)n-Cool (where n is 1 to 3, particularly preferably 2). remaining substituent R2 , R4, R5 and RvtoR= are preferably hydrogen or CH3; Preferably, the remaining substituents are the same.

Compounds of formula (I) of this type are particularly well suited for the treatment of tumors.

A particularly important group of ligands for the complexes used according to the invention is that It has a positive charge so that the complex produced is positively charged. this type The compounds are used, for example, for radiodiagnostic use, especially in the heart of warm-blooded species (humans and animals). Particularly suitable for diagnostic manifestations. Positive charges are represented by formulas (n), (I[a), (I lb) and (IV) or derived from the quaternary nitrogen atom of compounds of formula (1 ) or (III) can be present on the glue gantt, but also formula (II), (I [a), (IIb) and (rV) positively charged which can also be present on the glue Gantt Either can be derived from a substituent having a functional group. positive charge can be obtained, for example, by protonation or by quaternization of the nitrogen atoms present. Can be done. Particularly advantageous examples include formulas (n), (Ila), (nb) and (rV). All substituents (substituents R1 to RJ in formulas (■), (lIa), and (nb)) is a compound showing a methyl group.

Examples of substituents having positively charged functional groups are, for example, trimethylamino group or Alkyl groups combined with quaternary ammonium groups such as triethylamino groups, e.g. The formula -(CH2)n-N''R3 (wherein n is 1 to 3, particularly 2, and R is 1. alkyl having ~4 carbon atoms, especially methyl).

Particularly preferred compounds of formula (I) are R,=R3=R5=-CH, CH2Co Compounds in which n and R2=R, =R, =H and in the formula 1?1=R3=R5= −CJ(jJzN”(CT13)z and R2=l?, =t!, =H It is a thing.

The complexes used according to the invention are salts, hydroxides or salts of the radioactive metals involved in each case. or from aqueous solutions or suspensions of oxides and aqueous solutions or suspensions of ligands. Easily manufactured. The aqueous solution can be acidic, for example. For this general The amount used for formula (1), (II), (IIa), per 21 moles of metal rice is (Ilb) 2 moles of glue or 1 mole of ligand of formula (m) or (rV) It is such an amount that it exists. Preferably, a small excess of ligand is used.

To produce a technetium complex, e.g. technetium (■) ion is present Technetium hexafluoride or technetium can be first reduced as Starting with each solution of xachloride, then the aqueous solution with excess ligand It is possible to add

A portion of the radioactive metal or metal cation in the complex used according to the invention is It can be replaced by the corresponding non-radioactive isotope. For example, the complex releases Complexes of radioactive metals or metal cations and complexes of non-radioactive metals or metal cations It can exist in the form of a mixture with the body. In addition, non-radioactive metals or gold The genus cation and the radioactive metal or metal cation may be the same or different. can. For example, when radioactive iron isotopes are used, they are can exist together. In the production of products of this type, e.g. Forming a complex from a solution of iron(m) ions in the presence of radioactive iron(m) ions I can do it.

The complexes used according to the invention may be manufactured by the manufacturer or supplier. Can be done. However, they can also be used in X-ray laboratories or treatment laboratories to prepare solutions. They are often manufactured on-site from liquids.

The resulting aqueous complex solution can be used for radiodiagnosis and abscess treatment. Ingredients Physical applications include X-ray tomography, positron emission tomography and especially humans and animals. representation of the heart, and it is preferred to use positively charged complexes for this purpose. medical examination It is particularly advantageous to select complexes that are γ- or β1-emitters. . Alpha emitters are preferably used to inhibit tumors, such as cancer.

The complexes used according to the invention are used in the form of an aqueous solution. they are in different ways , especially by intravenous administration.

Example 1: All-cis-1,3,5-tris(2-carboxyethylamino)-2,4,6- Synthesis of cyclohexandriol All-cis-1,3,5-triammonio-2, 4,6-cyclohexandriol sulfate l mmol (0,334q ) in a small amount of water and applied to an ion exchange column (Dowex 1 x 4.5 0/100 mesh, OH type) packed on top. The eluate is a neutral reaction mixture. It was eluted with water until it had a compound. The basic fraction was concentrated in a rotary evaporator. . This solution of triaminone chlorhexanetriol l mmc+1 was added to acrylonitrile. Mixed with Tril 3 gaol (IM aqueous solution 3 mm+) and then heated under nitrogen for one week. I left it in the dark. By evaporation in a rotary evaporator the entire intermediate product is 1. ．． 3.5-1 Lis(2-noanoethylamino)-2,4,6-cyclohexando Riolu was obtained.

'[I NMR (90MHz, C20, po2): 2.97 ppm (t , 60).

3.49 ppm (t, 61'l), 3.60 ppm (+++, 31i) , 4.54 ppm (m.

311).

]3CNMR (62.9MHz, D, O, pD 3): 14.9 ppm, 4 0.6ppm, 57.0ppm, 63.2ppm, 1.17.4pl) I @.

pKl (approximately): 3.0.4.5.6.3゜The above nitrile was refluxed in concentrated hydrochloric acid. Hydrolysis was carried out by boiling for 6 hours. Evaporation in a rotary evaporator cis-1.3.5-)lis(2-carboxyethylammonio)-2,4, 6-Cyclohexandriol trichloride was obtained.

Take this into a small amount of water and neutralize it with potassium hydroxide solution to about I) H4,5. did. During this time, all-cis-1,3,5-tris(2-carboxyethylamino) -2,4,6-cyclohexane) l)ol was precipitated. Filter off the product and dilute dissolved in acid (pFl<3) and precipitated again by neutralization, filtered off and finally Dry under high vacuum.

Elemental microanalysis: Material formula: C1++HztNiOt+, +11: 393.39 Calculated value C45, 80% 8 6.92% N 10.68% Actual measurement @: C41, 50% 8 7.24% N 9.31% These values represent 2 water of crystallization per mole of product. ．． It corresponds to 8 moles.

'B NMR (200 Mllz, 020. acid): 2.951) I) (Il (t, 611).

3.53 ppm (t, 6B), 3.72 ppm (n+, 3Ft), 4.72 ppm (m.

3H).

13CNMR (200MHz, C20, acid) + 32.8 ppm. 43.5 1)pm.

59.6 ppn, 66.1 ppm, 176.9 ppm0 pK value (approx.) :　6.2.8.2.9.7゜Example 2: C59Fe] Iron(III) all-cis 1. ．． 3.5-tris(2-carboxylene) Synthesis of (ethylamino)-2,4,6-cyclohexandriol All-cis-1.3.5-1-lis(2-carboxyethylamino)-2,4,6 - Cyclohexanetriol (from Example 1) i small in 0.1M hydrochloric acid 2[]III. ’Fe(I[[)　(I((J’In IM, “FeC/3 (manufactured by Amersham) 1M FeC1* with 2 mCi 1 m/) l meal was added. KOH (approximately IM) with this transparent yellowish color. It was added gradually to the solution, which became a deeper yellow color during this time. Produced at approximately pH 3 Things started to completely settle out. Then alkali was added until the pH was about 4.5.

The precipitated [:89Fe]iron(m) all-cis-1.3.5-1-lith(2-carbo 04 sintering of (xylate ethylamino)-2,4,6-cyclohexandriol Filtered off on a disk, subsequently dissolved in 0, IM UCI and precipitated at pH 4.5. It was purified by evaporation. The product was finally dried under high vacuum.

Structural identification of non-radiolabeled products was made based on spectroscopic properties.

Analysis of the non-radioactively labeled complex shows that the formula is Cl5Hz4N10(IFe) It is concluded that

Example 3, All-cis-1,3,5-trihydroxy-2,4,6-tri-N-acetylamide Synthesis of non-chlorohexane Amine (from Example 1) 3.28 g (1,8,5 mol) in methanol 1 00ml and added 35ml (370mmo/) of acetic anhydride. This mixture The mixture was stirred at room temperature overnight. Methanol and excess acetic anhydride were removed in vacuo . The resulting product was recrystallized from ethanol and oxidized under high vacuum for 24 hours. Dry in the oven. Yield 86%, melting point 300°C.

Elemental microanalysis Substance formula: Cl5H21N306, Xi W: 303.3 Calculated value: C47, 52% H6, 98% N 13.85% Actual clay: C46, 21% H682% N 1.3.61%'HroR (200MHz, C20): 2.05 ppm (s, 3F, 3.97-4.04 (q, 2H).

13CNMR (200MHz, C20) + 176.4 ppm, 72.8 　T)I)Ill.

53.5ppn, 24.7 I)I)”.

Easily soluble in two solubility Example 4・ [59Fe]Iron(II[) all-cis-1,3,5-trihydroxy-2,4,6 -Synthesis of tri-N-acetylaminotalohexane 3.5-1-lihydroxydi-2,4,6-tri-N-acetyl Aminocyclohexane 1 Ygol was dissolved in about 20ml of 0.1M hydrochloric acid.

Fe (m) 1MFe in CEICILM (J! 30.5 min A’) 0.5a* ai was added along with “FeC et al. (Amersham) 211C1.

Next, the precisely calculated amount of KOH (iM) and Fe per hydrochloric acid Additionally, 8 equivalents of alkali were added at once (all>8). Continue checking with a pH meter while performing reverse neutralization using E[ClIM) until the pH is 5.0 ± 0.2. Shino;.

An uncharged iron complex with the composition Fe (+'13L2) (L = ligand) It precipitated. This complex is compatible with buffers at physiological pH and above. Soluble.

Structural identification of non-radiolabeled products was made based on spectroscopic properties.

From the analysis of the non-radioactively labeled complex, the formula is FeC24F139N601 z・8 It is concluded that it is LO.

Example 5D Gadolinium all-cis 1.3.5-tris(2-carboxylate ethyla Synthesis of (mino)-2,4,6-cyclohexandriol All-in-one 1. ．． 3.5-tris(2-carboxyethylamino)-2,4,6 - Cyclohexanetriol (from Example 1) 1 mmol to 1 mol/i' Dissolved in 3ml of hydrochloric acid. GdC13 (HCA! 1 wol/, e) m1 GdC13X 6nzO 100mg) i mxo (! was added. The pH of the clear colorless solution was gradually adjusted to 45 with Na0II (approximately 2 ol/l). . From this, initial turbidity occurred at pH 3, and a precipitate formed at pt+4.5. precipitated Gadolinium total cis 1.3.5-1-lis (2-carboquine 1 note ethyl) 2,4,6-cyclohexanetriol was filtered over 64 sintered discs. filtered and subsequently washed with distilled water. The product was finally heated to 40’C under high vacuum. Dry elemental trace analysis: Material formula: C+ 5FI24NaOeGd, MW: 547.62 Calculated value : C32,90% H442% N7.67% Gd 28.72% Actual value: C22.13% 8 6.58% N5.17% Gd 1.9. ], O% meter Sankeibon C22.03% H665% N 5. ], 44%Gd 19.23% (*15 H2O) These values correspond to 15 moles of water of crystallization per mole of product.

Summary book Radiotherapy for radiodiagnosis and tumor treatment, and for the production of these agents. Radioactive metal ions and all-cis-1,3,5-1-lyamino-2,4,6-1-lihy of droxycyclohexane, its derivatives, salts or complexes with quaternary ammonium salts use.

international search report international search report

Claims (15)

[Claims] 1. Radiation for radiodiagnosis and tumor therapy and for the production of their agents. metal ion and general formula (I) as a ligand ▲There are mathematical formulas, chemical formulas, tables, etc.▼I [In the formula, the symbols R1, R2, R3, R4, R5 or R6 are the same or different hydrogen atom, alkyl group or -CO-alkyl group (wherein the alkyl or The alkyl in the -CO-alkyl group has 1 to 18 carbon atoms, and the alkyl and -CO-alkyl groups are each independently one or more of the same or all-cis-1,3,5-tria having Mino-2,4,6-trihydroxycyclohexane or its derivatives, inorganic or are their salts with organic, pharmacologically customary acids, or pharmaceutically usable anions. and general formula (II), (IIa) or (IIb) ▲ Numerical formulas, chemical formulas, tables, etc. ▼(II)▲There are mathematical formulas, chemical formulas, tables, etc.▼(IIa)▲Mathematical formulas, chemical formulas, There are tables, etc. ▼ (IIb) (In the formula, R1 to R6, R7, R8 and R9 are independently of each other, having the above definitions unsubstituted or substituted representing an alkyl group or a -CO-alkyl group) salt, or general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼III or ▲There are mathematical formulas, chemical formulas, tables, etc. S▼IV (wherein the substituents on the nitrogen atom are independently H or CH3) All-cis-1,3,5-triamino-2,4,6-trihydroxycyc Use of complexes with lohexane derivatives. 2. claim, characterized in that the radioactive metal ion is an α-, β- or γ-ray emitter; Use as described in claim 1. 3. Radioactive metal ions include iron, copper, gallium, yttrium, ruthenium, and techne. thium, rhodium, indium, dysprosium, samarium, thulium, i characterized by being an ion of a radioactive isotope of terbium or rhenium, Use according to claim 1 or 2. 4. Positively charged especially for cardiac radiodiagnostic indication or for the manufacture of agents of it Use according to any one of claims 1 to 3, characterized in that a complex is used. . 5. Liga of formula (II), (IIa), (IIb) or (IV) according to claim 1 5. Use according to claim 4, characterized in that a complex with a compound is used. 6. The groups R1 to R9 in formulas (II), (IIa) and (IIb) are each methyl and that the substituent on the nitrogen atom of formula (IV) is a methyl group. Use according to claim 5, characterized in that: 7. Groups R1 to R6 in formulas (II), (IIa) and (IIb) are methyl groups; and the radicals R7, R8 and R9 are each H. Use as described in 5. 8. The alkyl group or -CO-alkyl group may coordinately bond to the metal ion. any one of claims 1 to 4, characterized in that it contains one or more functional groups that can Uses as described in Section. 9. At least one of the groups R1, R3 and R5 has the general formula -(CH2)n-N■(R)3 (wherein n=1, 2 or 3, especially 2 and R is 1, 2, 3 or 4 carbon atoms) ) and the groups R2, R4 and R6 are hydrogen atoms; or an alkyl group having 1 to 18 carbon atoms; 5. Use according to claim 4, characterized in that the use is characterized in that a. 10. The groups R1, R3 and R5 are functional groups and have the general formula -(CH2)n-COO H (wherein n=1, 2 or 3, especially 2) and the group R 2, R4 and R6 to R9 are each H, general formula (I), (II), (II The method according to claims 1 to 3, characterized in that the ligand of a) or (IIb) is used. Use as described in any one of the above. 11. 11. The use according to claim 10 for treating a tumor or producing a drug thereof. 12. General formula (I), (II), (as defined in claim 1, 7, 8, 9 or 10) Aqueous solutions or solutions of derivatives of IIa), (1Ib), (III) or (IV) The dispersion is reacted with an aqueous solution or dispersion of a radioactive metal salt, hydroxide or oxide. of radioactive metal ions for radiodiagnosis and tumor treatment, characterized by Method for producing the complex. 13. Using salts, hydroxides or oxides of metals that are α, β or γ-ray emitters 13. The method according to claim 12, characterized in that: 14. Iron, copper, gallium, yttrium, ruthenium, technetium, rhodium , indium, dysprosium, samarium, thulium, ytterbium or A metal salt, hydroxide or oxide consisting of one or more radioactive isotopes of rhenium. Method according to claim 12 or 13, characterized in that it is used. 15. Claims 12 to 1 for producing an agent suitable for radiodiagnosis or tumor treatment. 4. Prepare an aqueous solution obtained as described in any one of paragraphs 4 and then add it as appropriate. according to any of claims 12 to 14, characterized in that it is mixed with customary pharmaceutical additives. The method described in item 1.