DE3621025A1 - Novel complexing agents and processes for their preparation - Google Patents

Abstract

Compounds of the general formula I <IMAGE> in which V<1> and V<2> are identical or different and in each case denote a COOH or <IMAGE> group, in which R<6> stands for a straight- or branched-chain alkyl radical having 2 to 7 carbon atoms, which is substituted by 1 to 5 hydroxyl groups and R<7> stands for a hydrogen atom, a straight- or branched-chain alkyl radical having 1 to 7 carbon atoms or an alkyl radical having 2 to 7 carbon atoms, which is substituted by 1 to 5 hydroxyl groups, R<1> denotes a hydrogen atom or a CH2COOH group, R<2> and R<3> denote a (CH2)m group where m denotes 0 or 1 if R<4> and R<5> simultaneously in each case stand for a hydrogen atom, R<4> and R<5> denote a -CH2-CH2-(CH2)m group where m denotes 0 or 1, if R<2> and R<3> simultaneously in each case stand for a hydrogen atom, and their salts with inorganic and/or organic bases or amino acids, are useful complexing agents.

Description

The invention relates to new ones suitable as complexing agents Aminopolycarboxylic acids and process for their preparation.

The present invention relates to

• a) the compounds of the general formula I mentioned in the claims and containing a pyrrolidine or piperidine ring, wherein
  V ¹ and V ^{2 are the} same or different and are each one wherein
  R ^{6 is} a straight-chain or branched-chain alkyl radical having 2 to 7 carbon atoms which is substituted by 1 to 5 hydroxyl groups and
  R ^{7 represents} a hydrogen atom, a straight-chain or branched-chain alkyl radical having 1 to 7 carbon atoms or an alkyl radical having 2 to 7 carbon atoms which is substituted by 1 to 5 hydroxyl groups,
  R ^{1 is} a hydrogen atom or a CH ₂ COOH group,
  R ² and R ^{3 are} a (CH ₂ ) _m group with m meaning 0 or 1, when R ⁴ and R ^{5 are} each a hydrogen atom,
  R ⁴ and R ^{5 are} a -CH ₂ -CH ₂ - (CH ₂ ) _m group with m in the meaning of 0 or 1, when R ² and R ^{3 are} each a hydrogen atom,
  means, and their salts with inorganic and / or organic bases or amino acids,
• b) process for the preparation of these complexing agents and
• c) the use of these complexing agents z. B. for production therapeutically and diagnostically valuable metal complexes.

The use of complexing agents or complexes or their Salting in medicine has been known for a long time. As examples are mentioned:

Complexing agents as stabilizers of pharmaceutical preparations, complexes and their salts as auxiliaries for the administration of poorly soluble ions (e.g. iron), complexing agents and complexes (preferably calcium or zinc), optionally as salts with inorganic and / or organic bases, as antidots are known for detoxification in the event of accidental incorporation of heavy metals or their radioactive isotopes and complexing agents as auxiliary agents in nuclear medicine using radioactive isotopes such as ^99m Tc for scintigraphy.

In the patents EP 71 564 and EP 1 30 934 have recently become paramagnetic complex salts as diagnostics, have mainly been proposed as NMR diagnostics. All known complexing agents, complexes and their Salts cause problems in their clinical application in terms of compatibility, selectivity of binding and stability. These problems are all the more pronounced the higher the complexing agents and those derived from them Products must be dosed. For example, limits the insufficient in the treatment of metal poisoning Kidney tolerance of the complexing agents available today as well as their tendency for ions essential for the organism to tie up the use. The useful in itself Use of heavy elements as part of parenteral X-ray contrast media to be administered have so far failed insufficient compatibility of such compounds.  

For those previously proposed for magnetic resonance imaging or tested paramagnetic, contrast-enhancing Is the distance between the effective and the substances in animal experiments the toxic dose is often relatively narrow.

There is therefore a need for various purposes everything better tolerated, but also stable, well soluble and sufficiently selective complexing agents. The new compounds of the general described here Formula I meet these requirements.

As starting substances for the production of these compounds serve e, e-3,4-diamino and e, e-2,5-bis (aminomethyl) pyrrolidine as well as e, e-3,5-diamino and e, e-2,6-bis (aminomethyl) - piperidine, that is to say amines of the general formula II

wherein R ² , R ³ , R ⁴ and R ^{5 have} the meaning given above, which are known from the literature (J. Pharm. Sci. 58, 1038 (1969)) or by catalytic hydrogenations in a manner known per se, for. B. with rhodium / carbon or Nishimura contact as a catalyst (Houben-Weyl, Methods of Organic Chemistry, Vol. 4 / 1c, p. 256, Georg Thieme-Verlag Stuttgart, New York 1980, F. Zymalkowski, Catalytic Hydrogenations, Ferdinand Enke-Verlag Stuttgart 1965) from corresponding aromatic precursors (Rec. De Travau de Chim. Des Pays-Bas 72,569 (1953), Ann. Chem. 537 (1978), J. Pharm. Soc. Japan 79, 549 (1959)) be preserved.

Subsequent alkylation with haloacetic acids or their esters of the formula

HalCH ₂ COOR ⁸ ,

where Hal represents chlorine, bromine or iodine and R ^{8 represents} a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, either the corresponding tetracarboxylic acid (R ¹ = H) or its ester or the corresponding pentacarboxylic acid (R ¹ = CH ₂ COOH) or their esters.

Suitable auxiliary bases are all those skilled in the art for alkylation reactions known bases, such as alkali and Alkaline earth carbonates, alkali and alkaline earth hydrogen carbonates, polymeric anion exchangers and the usual organic ones Auxiliary bases such as B. triethylamine, tetramethylpiperidine, Pentamethylpiperidine, proton sponge and tetramethylguanidine. Preferred for the preparation of the tetraacetic acid-substituted Compounds are lithium carbonate, sodium carbonate and Ambelite LA2, for the production of pentaacetic acid residues bearing compounds potassium carbonate, tetra- and pentamethylpiperidine.

All solvents which can be used for alkylations are suitable as solvents Solvents, preferably tetrahydrofuran, dimethylformamide, Dimethylacetamide and dimethyl sulfoxide.

The compounds of the general formula I according to the invention with R ¹ in the meaning of a hydrogen atom, ie the tetraacetic acid-substituted compounds, can also be catalytically hydrogenated by the abovementioned methods of the corresponding aromatic tetracarboxylic acids or their esters (Chem. Reports 117, 948 (1984 )) getting produced. Subsequent N-alkylation in a manner known per se provides the desired pentaacetic acid-substituted compounds of the general formula I.

The necessary saponification of the possibly occurring Acetic acid ester groups are prepared according to those known to the person skilled in the art Methods carried out, for example with basic catalysts such as alkali or alkaline earth carbonates or hydroxides.

The introduction of amide groups for the preparation of compounds of the general formula I in which V ¹ and / or V ^{2 represent} a CONR ⁶ R ⁷ group takes place by partial conversion of carboxyl groups of the aminotetra- and aminopentacarboxylic acids obtained in the manner described above into mono - or polyhydroxyalkylamide groups. All synthesis possibilities known to the person skilled in the art are possible for this process. An example of this is the reaction of the anhydrides or esters of the general formula III to V

with R ⁹ as an alkyl radical with 1 to 4 carbon atoms,

wherein Y and Z together represent an oxygen atom or Y represents a hydroxyl group and Z represents the OR ^{9 group} , with mono- or polyhydroxyalkylamines of the general formula VI

where R ^{6 represents} a straight or branched chain mono- or polyhydroxyalkyl radical and R ^{7 represents} a hydrogen atom, a lower straight or branched chain optionally mono- or polyhydroxylated hydrocarbon radical. These radicals contain 1 to 7, preferably 2 to 4 carbon atoms and 1 to 5, preferably 2 to 4 hydroxyl groups. Examples of suitable hydroxyalkyl radicals are: 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) ethyl, 2,3-dihydroxypropyl, tris (hydroxymethyl) methyl, 2,3-dihydroxy-1-hydroxymethylpropyl, 2,3, 4,5,6-pentahydroxyhexyl-N-methyl and preferably 2-hydroxyethyl, 2-hydroxy-1- (hydroxymethyl) ethyl, 2,3-dihydroxypropyl and 2,3,4-trihydroxybutyl. The polyhydroxyalkylamines can advantageously also be used in a protected form for the reaction, e.g. B. as O-acyl derivatives or as ketals. This is especially true when these derivatives are more convenient and cheaper to produce than the polyhydroxyalkylamines themselves. A typical example is 2-amino-1- (2,2-dimethyl-1,3-dioxolan-4-yl) ethanol, which Acetonide of 1-amino-2,3,4-trihydroxybutane, produced according to DE-OS 31 50 917.

The subsequent removal of the protective groups is easy and can e.g. B. by treatment with an acidic ion exchanger done in aqueous ethanolic solution.

The preparation of the acid anhydrides of the general formula III can be done by known methods, e.g. B. after in US Patent 36 60 388 or described in DE-OS 16 95 050 Procedure with acetic anhydride in pyridine.  

In certain cases, however, it is particularly advantageous the elimination of water with carbodiimides in a suitable Solvents such as B. dimethylformamide or dimethylacetamide, to be carried out gently.

The preparation of the monoanhydrides of the formula V can, for example after the in J.A.O.C.S. 59 (2) 105 (1982), see C.A. 96 164556 u (1982) described methods by partial Hydrolysis of bis-anhydrides take place.

The conversion of the acid anhydrides to the invention Hydroxyalkylamides are carried out in the liquid phase. Suitable reaction media are, for example, water, dipolar aprotic solvents such as acetonitrile, N-methylpyrrolidone, Dimethylformamide, dimethylacetamide and the like or mixtures thereof. The reaction temperatures are between approx. 0 ° C to 100 ° C, with temperatures of approx 20 ° to 80 ° C are preferred. The response times are between 0.5 hours and 2 days, preferably between 1 hour and 36 hours.

The preparation of the esters of the general formulas IV and V takes place in a known manner, e.g. B. IV and V according to in R. A. Guilmette et al., J. Pharm. Sci. 68, 194 (1979) and IV by the method described in U.S. Patent 3,497,535.

The aminolysis of the esters takes place in the liquid phase, e.g. B. in a suitable higher-boiling solvent such as dimethylformamide, Dimethylacetamide or dimethyl sulfoxide. The reaction temperatures are around 20 ° C to 200 ° C, temperatures from 100 ° C to 180 ° C are preferred. The response times are between 2 hours and 2 days, reaction times between 4 and 36 hours are preferred are.  

In addition, all methods known to the person skilled in the art can be used for the conversion of carboxyl groups into amide groups for synthesis the complexing agent of the general Formula I can be used.

The amides according to the invention obtained in this way can also contain metal chelates form, which are still very high binding constants have d. H. they have good stability similar to that like that of the polyaminopolycarboxylic acids from which they are derived deduce. Apparently, the oxygen functions of the introduced hydroxyalkylamide groups as new coordination points serve for complexation. This leads to a favorable stability of the in the physiological pH range Application coming aqueous solutions of the metal complexes.

Furthermore, the new complexing agents according to the invention are surprisingly sufficiently selective for biologically non-essential heavy metals, so that, for example, the Cu ⁺⁺ , Co ⁺⁺ and Fe ⁺⁺ ion concentrations in the body are not reduced in an unacceptable manner.

The following exemplary embodiments serve to provide more details Explanation of the method and use of the process products.  

EXAMPLE 1 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1-piperidine acetic acid

31.6 g (55.0 mmol) of 2,6-bis [N, N-bis (ethoxycarbonylmethyl) aminomethyl] - 1-piperidine acetic acid ethyl ester are in 160 ml Dioxane dissolved and the solution diluted with 160 ml of water. Add to this solution with stirring and slow heating 30.6 ml of 11 normal sodium hydroxide solution were added dropwise to 80 ° C. It is held at 80 ° C for 1.5 hours and after cooling Adjusted to pH 2 with concentrated hydrochloric acid at 20 ° C. The acidic solution is on a cation exchanger Type Amberlite IR 120 given, the exchanger with plenty Washed water and then with semi-concentrated Ammonia elutes. The one obtained by evaporating the eluate The crude product is again dissolved in 400 ml of water and thoroughly Addition of IR 120 adjusted to pH 2.6. The exchanger is suction filtered and the aqueous solution evaporated. The residue (18.1 g) is dissolved in 170 ml of methanol and 10 ml Dissolved water with heating and slowly cooled. 13.8 g of colorless crystals (57% of theory) are obtained. melting point 189-191 ° C.

Analysis:

C 47.11 H 6.28 N 9.70 (calc.)
C 47.02 H 6.30 N 9.64 (found)

The starting material is produced in the following way:  

a) 2,6-bis (aminomethyl) piperidine trihydrochloride

123.3 g (0.5 mol) of 2,6-bis (aminomethyl) pyridine trihydrochloride (Annalen der Chemie 537-544 (1978)) are dissolved in 2.5 ml Dissolved water and with the addition of 25 g rhodium / coal as Catalyst in an autoclave at a maximum of 50 ° C and 16 bar initial pressure hydrogenated within 1 hour. The catalyst will filtered off and the colorless filtrate to dryness in vacuo constricted. The oily residue is in 1250 ml of methanol dissolved with heating and then evaporated again. The foam obtained is successively only in 600 ml of methanol and then stirred in 600 ml of acetonitrile at 25 ° C, filtered and dried in vacuo. 109 g (86% of theory) are obtained. a colorless, highly hygroscopic powder of melting point 263 to 264 ° C.

Analysis:

C 33.28 H 7.98 N 16.64 Cl 42.10 (calc.)
C 33.31 H 7.91 N 16.50 Cl 42.13 (found)

b) 2,6-bis [N, N-bis (ethoxycarbonylmethyl) aminomethyl] -1- piperidine acetic acid ethyl ester

50.52 g (200 mmol) of 2,6-bis (aminomethyl) piperidine trihydrochloride are in 1200 ml of dimethylacetamide with stirring 165.8 g (1.2 mol) of potassium carbonate were added. After encore of 167 ml (1.5 mol) of ethyl bromoacetate is used for 24 hours heated to 100 ° C. After cooling to 25 ° C, the mixture is filtered and the filtrate was concentrated in vacuo. You get as residue a low viscosity oil that is absorbed in 1200 ml of ethyl acetate becomes. The organic phase is washed 4 times with 300 ml each Water, dries over sodium sulfate, filtered and concentrated the filtrate in a vacuum. You get a raw product, the  via column chromatography (material: silica gel) with methylene chloride / Methanol (95: 5) is cleaned as the eluent. 78 g (68% of theory) of light oil are obtained, the Purity is determined by gas chromatography.

Analysis:

C 56.53 H 8.26 N 7.32 (calc.)
C 56.44 H 8.12 N 7.39 (found)

EXAMPLE 2 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] piperidine

28.4 g (50 mmol) of 2,6-bis [N, N-bis (ethoxycarbonylmethyl) - aminomethyl] -1-piperidine hydrobromide in 200 ml of dioxane / Water (1: 1) dissolved.

With stirring and heating to 80 ° C, 27 ml of 11 normal Sodium hydroxide solution added dropwise and the solution at 80 ° C. for 1.5 hours held. After cooling to room temperature, it is concentrated Acidified hydrochloric acid to pH 2 and the acidic solution on an amberlite IR 120 cation exchanger given. The exchanger is washed with plenty of water and then eluted with semi-concentrated ammonia. Evaporation of the eluate gives a crude product, which is dissolved again in 300 ml of water. Subsequently the solution is adjusted to pH 3.0 with IR 120. The exchanger is suctioned off and the solution is concentrated in vacuo. The residue is recrystallized from methanol / water (10: 1). 13.5 g (72% of theory) of a colorless product are obtained Crystals from melting point 129 to 132 ° C.

Analysis:

C 48.00 H 6.71 N 11.19 (calc.)
C 47.78 H 6.97 N 11.02 (found)

The starting material is produced in the following way:

a) 2,6-bis [N, N-bis (ethoxycarbonylmethyl) aminomethyl] -1- piperidine hydrobromide

25.2 g (100 mmol) of 2,6-bis (aminomethyl) piperidine trihydrochloride (prepared according to Example 1a) in 600 ml of dimethylacetamide suspended and with 61.1 ml (550 mmol) of ethyl bromoacetate and 410 ml (900 mEquiv) liquid anion exchanger Amberlite LA 2 offset. It will be open 24 hours Heated 60 ° C, after cooling to 25 ° C the solvent removed and the oily residue is stirred with 2 l of n-pentane. A colorless precipitate is obtained, which after filtration washed several times with n-pentane and then in vacuo is dried at 40 ° C. 38.9 g of a crude product are obtained, which is recrystallized from 400 ml of ethyl acetate. Man receives 31 g (55% of theory) of colorless crystals of Melting point 116 to 117 ° C.

Analysis:

C 48.49 H 7.45 N 7.39 Br 14.06 (Ber.)
C 48.80 H 7.51 N 7.20 Br 13.81 (found)

The desired tetraester (hydrobromide) can be same way using lithium or sodium carbonate as an auxiliary base.  

EXAMPLE 3 2,6-bis [N, N-carboxymethyl-N- (2,3-dihydroxy-N-methylpropyl- carbamoylmethyl) aminomethyl] -1-piperidine acetic acid

4.0 g (10 mmol) of 2,6-bis (2,6-dioxomorpholino-methyl) -1-piperidine acetic acid, dissolved in 50 ml of dry N-methylpyrrolidone with 2.1 g (20 mmol) of N-methylaminopropane-2,3-diol transferred. The solution is heated to 60 ° C. for 5 hours, stir for 16 hours at room temperature and remove that Solvent in a vacuum. The residue is stirred in 100 ml of diethyl ether. A colorless precipitate is obtained, which is filtered off and dried in vacuo. You get 4.6 g (76% of theory) of a white powder of melting point 104 to 108 ° C.

Analysis:

C 49.42 H 7.47 N 11.53 (calc.)
C 49.27 H 7.19 N 11.67 (found)

The starting material is produced in the following way:

a) 2,6-bis (2,6-dioxomorpholino-methyl) -1-piperidine acetic acid

4.3 g (10 mmol) of 2,6-bis [N, N-bis (carboxymethyl) aminomethyl] -1-piperidine acetic acid (prepared according to Example 1) are dissolved in 80 ml of dimethylformamide with heating and the solution is then heated to 5 ° C. chilled. 4.2 g (20 mmol) of dicyclohexylcarbodiimide, solid, are added with stirring and cooling. Upon further cooling for 12 hours, the resulting dicyclohexylurea separates out as a white, voluminous precipitate. It is filtered and the filtrate in vacuo at max. Concentrated at 50 ° C. A light yellow oil is obtained, from which the desired anhydride can be precipitated by stirring with various organic solvents, preferably with organic ethers such as diethyl ether. A white powder is obtained which, however, hydrolyzes in air. The desired anhydride is therefore detected in the dimethylformamide solution by IR spectroscopy (anhydride bands at 1820 and 1780 cm ^-1 and COOH at 1640 cm ^-1 ), the solution is concentrated in vacuo and the residue is reacted with the hydroxyalkylamines in the desired amount Solvent, preferably in N-methyl-2-pyrrolidone.

EXAMPLE 4 2,6-bis {N-carboxymethyl-N- [bis (2-hexoxyethyl) carbamoylmethyl] - aminomethyl} -1-piperidine acetic acid

9.9 g (25 mmol) of 2,6-bis (2,6-dioxomorpholinomethyl) -1-piperidine acetic acid (prepared according to Example 3) dissolved in 150 ml of dry dimethylformamide, 5.25 g (50 mmol) of diethanolamine are added and the solution heated to 50 ° C for 5 hours. You stir 16 Hours at room temperature and removes the solvent in a vacuum. The residue is stirred in 150 ml of diisopropyl ether, whereby a colorless precipitate is obtained. To Filtration and drying in vacuo gives 12.2 g (82% of theory) of a colorless powder with a melting point of 141 up to 146 ° C.

Analysis:

C 49.42 H 7.46 N 11.53 (calc.)
C 49.70 H 7.32 N 11.41 (found)

EXAMPLE 5 2,6-bis [N-carboxymethyl-N- (2,3,4-trihydroxybutylcarbamoylmethyl) - aminomethyl] -1-piperidine acetic acid

4.0 g (10 mmol) of 2,6-bis (2,6-dioxomorpholinomethyl) -1-piperidine acetic acid (prepared according to Example 3) dissolved in 50 ml dry N-methylpyrrolidone, with 3.2 g (20 mmol) 2-Amino-1- (2,2-dimethyl-1,3-dioxolan-4-yl) ethanol added and heated to 60 ° C for 4 hours. Then stir 16 Hours at room temperature after, the solvent is removed in vacuo and the residue is stirred in 150 ml of diisopropyl ether. The precipitate is filtered and in 150 ml of water added. You acidify with concentrated Hydrochloric acid to pH 1, stirred overnight at room temperature and constricts in a vacuum. The residue is dissolved several times in diisopropyl ether stirred, filtered and dried in vacuo. 4.3 g (68% of theory) of a colorless product are obtained Powder with a melting point of 112 to 115 ° C.

Analysis:

C 46.94 H 7.09 N 10.95 (calc.)
C 46.71 H 7.18 N 11.10 (found)

Claims (12)

1. Compounds of the general formula I wherein
V ¹ and V ^{2 are the} same or different and are each one wherein
R ^{6 is} a straight-chain or branched-chain alkyl radical having 2 to 7 carbon atoms which is substituted by 1 to 5 hydroxyl groups and
R ^{7 represents} a hydrogen atom, a straight-chain or branched-chain alkyl radical having 1 to 7 carbon atoms or an alkyl radical having 2 to 7 carbon atoms which is substituted by 1 to 5 hydroxyl groups,
R ^{1 is} a hydrogen atom or a CH ₂ COOH group,
R ² and R ^{3 are} a (CH ₂ ) _m group with m meaning 0 or 1, when R ⁴ and R ^{5 are} each a hydrogen atom,
R ⁴ and R ^{5 are} a -CH ₂ -CH ₂ - (CH ₂ ) _m group with m in the meaning of 0 or 1, when R ² and R ^{3 are} each a hydrogen atom,
means, and their salts with inorganic and / or organic bases or amino acids. 2. Compounds according to claim 1, characterized in that V ¹ and V ² each represent a COOH group. 3. Compounds according to claim 1, characterized in that V ¹ and V ² each for one stands. 4. Compounds according to claim 1, characterized in that V ¹ for a COOH and V ² for a stands. 5. Compounds according to claim 1, characterized in that R ^{1 represents} a hydrogen atom. 6. Compounds according to claim 1, characterized in that R ^{1 represents} a CH ₂ COOH group. 7. Compounds according to claim 1, characterized in that R ² and R ^{3 are} a (CH ₂ ) _m group with m in the meaning of 0 or 1 and at the same time R ⁴ and R ⁵ each represent a hydrogen atom. 8. Compounds according to claim 1, characterized in that R ⁴ and R ^{5 are} a -CH ₂ -CH ₂ - (CH ₂ ) _m group with m in the meaning of 0 or 1 and simultaneously R ² and R ³ each for a hydrogen atom. 9. Compounds according to claim 1, characterized in that m has the meaning 0. 10. Compounds according to claim 1, characterized in that m has the meaning 1. 11. Use of the compounds according to claim 1 to 10 as a complexing agent. 12. A process for the preparation of compounds of the general formula I according to claim 1, characterized in that amines of the general formula II in which R ² , R ³ , R ⁴ and R ^{5 have} the meaning given above, with a compound HalCH ₂ COOR ⁸ , in which Hal represents chlorine, bromine or iodine and R ^{8 represents} a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, alkylated in the presence of a base and then splitting off existing alkyl radicals R ⁸ by saponification and, if desired, the resulting compounds with V ¹ and V ² in the meaning of COOH groups via the corresponding bisanhydrides of the general formula III or compounds of the general formula IV with R ⁹ as an alkyl radical with 1 to 4 carbon atoms,
or compounds of the general formula V wherein Y and Z together represent an oxygen atom or Y represents a hydroxy group and Z represents the OR ^{9 group} , with an amino alcohol of the general formula VI implements
and if desired the salts with inorganic and / or organic bases or amino acids are prepared from the acids.