The metal complexes with the bicyclic polyaminoamide, method of their production and their use in medicine to obtain an image

 

(57) Abstract:

The invention relates to metallogenica derivative containing four nitrogen atom of the macrocycle, fused with the pyridine cycle, methods for their preparation and their use in medicine for image acquisition. The technical result is to obtain new compounds with relaksirutemu r110-15 times higher than relaxruimte commercially available compounds not only in the case of a magnetic field of 0.5 T and 1 T, fields, most modern devices for image acquisition, and even 1.5 T field the most effective devices. 4 N. and 11 C.p. f-crystals.

The present invention relates to metallogenica derivative containing four nitrogen atom of the macrocycle, fused with the pyridine cycle, methods for their preparation and their use in medicine to obtain the image.

It was repeatedly suggested usage for image acquisition chelates of some derivatives of this condensed macrocycle with paramagnetic or radioactive cation. You can refer to applications for European patents EP-A-0438206, EP-A-0570575 and EP-A-0579802, which describes compounds of formula:

in which the group forming a relationship with the biological macromolecule.

Among these compounds, the compound in which a = b = CH, R = H, X = CO2M = Gd, called RST, was the object of in-depth studies in Inorganic Chemistry, 36 (14), 2992-3000 (1997), and Magn. Reson. Chem., 36, 200-208 (1998); the authors particularly noted that RTA is remarkable in that it has a particularly high longitudinal relaksirutemu r1as she is about two times higher than that of gadolinium chelates used as a contrast products to obtain images by magnetic resonance in the case of man.

It is known that r1characterize the efficiency of paramagnetic products, generating strong contrast of the images, and especially of interest and unexpected is the fact that paramagnetic products according to the invention have relaksirutemu r110-15 times higher than relaxruimte commercially available compounds not only in the case of a magnetic field of 0.5 T and 1 T, fields, most modern devices for image acquisition, and even 1.5 T field the most effective devices.

As these new chelates, in addition to their favorable magnetic properties, are stabilnego, a good therapeutic index and the fact that depending on the nature of the group R they may have excellent vascular delay or specificity to the body, they can preferably be used in the case of man as a contrast products to obtain images by magnetic resonance in medicine, when a metal ion is radioactive element.

The present invention relates to metallogenica with the compound of the formula (I):

in which R denotes a group of formula (II):

and Z represents a relationship or a group selected from the groups CH2CH2-CO-NH or

(CH2)2-NH-CO;

Z' is a bond or a group selected from the groups O, S, NQ, CH2, CO, CO-NQ, NQ-CO., NQ-CO-NQ, CO-NQ-CH2-CO-NQ;

Z" means the bond or group selected from the groups CO-NQ, NQ-CO, CO-NQ-CH2-CO-NQ;

p and q denote integers whose sum is from 0 to 3;

R1, R2, R3, R4and R5independently from each other, are selected from the groups H, Br, Cl, I, CO-NQ1Q2and NQ1-CO-Q2and

Q1and Q2identical or different, denote H or (C1-C6)-alkyl, Forex is doroppu; or R1, R3and R5, independently of one another, denote H, Br, Cl or I;

and R2and R4indicates a group of the formula (III):

where Z'" means a group selected from the groups CO-NQ, CONQ-CH2, CO-NQ-CH2-CO-NQ, CO-NQ-(CH2)2-NQ-CO and NQ-CO-NQ

R'1, R'3and R'5identical or different, denote H, Br, Cl or I;

and Q'land Q'2identical or different, denote H or (C1-C6)-alkyl, possibly interrupted by an atom or atoms of oxygen;

Q denotes H or (C1-C4)-alkyl;

alkyl groups optionally can be mono - or polyhydroxyalkane.

Metal ions can be paramagnetic, such as Gd3+, Fe3+, Tb3+, MP2+, Dy3+or IG3+or radioactive: such as99mTC67Ga or111In; ions, forming a less stable chelates, which allow to proceed the reaction Parametrierung, such as CA2+or Zn2+are also part of the invention; paramagnetic chelates with Gd3+and Mn2+especially suitable for obtaining images by magnetic resonance. Especially preferred are paramagnetic chelates with Gd1-R5at the same phenyl nucleus together included 6-20 groups HE or that any present group CONQ1Q2or optional group CONQ'1Q'2contained 6-10 groups IT; still, it is preferable that the radicals R2and R4were the same and meant CO-NQ1Q2, each of which includes 6-10 groups HE is, or means a group of the formula (III), in which each CONQ'1Q'2contains 6-10 groups; preferred compounds in which R1, R3and R5choose among the atoms of iodine or bromine, and R'1, R'3and R'5when they are present.

Relaksiruet compounds and their pharmacokinetics in vivo especially depend on the number contained in the phenyl nuclei. For example, you can distinguish between the compounds in which p and q equal to 0, especially when R2and R4mean CO-NQ1Q2and compounds in which the sum of p and q is 1-3 or better 1 or 2 and R2and R4mean or not the radicals of formula (III).

When in compounds of formula (I) R2and R4mean CONQ1Q2then Q1and Q2preferable are (C2-C6)-alkyl groups, possibly interrupted by atom color is H, and among them, preferred those in which Z denotes CH2or CH2N, Z' represents a group chosen among CONH, CONHCH2CONH, NHCONH, and Z stands for a group selected among CONH and CONHCH2CONH, as well as the remainder Z'", when present, means CONH or CONHCH2CONH.

Finally, another special group of compounds is the group in which p and q is 1, Z denotes CH2or CH2CONH, Z' and Z" is chosen among CONH and CONHCH2CONH and R2and R4mean CONQ1Q2with R1, R3, R5preferably selected among the Br and I.

Other preferred compounds are the compounds listed in PP(i) to (ix) below:

(i) chelate compounds of formula (I) in which p and q equal to 0 and2and R4that is the same mean-CO-NQ1Q2and each group-CO-NQ1Q2includes 6-10 groups;

(ii) chelate compounds of formula (I) in which p and q are 0;1, R3, R5are the same and they are chosen among the Br and I; and R2and R4that is the same mean-CO-NQ1Q2and each group-CO-NQ1Q2includes 6-10 groups;

(iii) chelate compounds of formula (I), in which the sum of p + q n the formula (III). Of these compounds are preferred those in which the sum of p + q is 1 or 2;

(iv) chelate compounds of formula (I), in which the sum of p + q is not 0; R1, R3, R5,are the same and they are chosen among the Br and I; and R2and R4that is the same mean-CO-NQ1Q2and each of R2and R4includes 6-10 groups-HE. Of these compounds are preferred those in which the sum of p + q is 1 or 2;

(v) the chelate compounds of the formula (I) in which Z denotes CH2or CH2-CO-NH; Z' represents a group chosen among CO-NH, CO-NH-CH2-CO-NH and NH-CONH; Z stands for a group selected among CO-NH, and CO-NH-CH2-CO-NH; R2and R4that is the same mean-CO-NQ1Q2and each of R2and R4includes 6-10 groups-HE; and R1, R3and R5are the same and they are chosen among the Br and I. of these compounds are preferred those in which the sum of p + q is 1 or 2;

(vi) the chelate compounds of the formula (I) in which Z denotes CH2or CH2-CO-NH; Z' represents a group chosen among CO-NH, CO-NH-CH2-CO-NH, NH-CONH; Z stands for a group selected among CO-NH, and CO-NH-CH2-CO-NH; group Z'", when it is present, UB>2and R4mean CONQ1Q2and Q1and Q2represent polyhydroxyalkane, possibly interrupted by oxygen atom (C2-C6)-alkyl groups;

(viii) the chelate compounds of the formula (I) in which Z denotes CH2or CH2-CO-NH;

Z' and Z" is chosen among CO-NH, and CO-NH-CH2-CO-NH, p and q are equal to 1 and R2and R4mean CONQ1Q2. Of these compounds are preferred those in which:

- R2and R4together include 6-20 groups-HE; or

-R1, R3and R5are the same and they are chosen among the Br and I; and each of R2and R4includes 6-10 groups;

(ix) the chelate compounds of the formula (I), in which the sum of p + q is 0; R2and R4answer the formula (III) and R1, R3and R5are the same and they are chosen among the Br and I.

The invention relates also to a method for producing compounds of formula (I), which consists of:

in the introduction to the interaction of the condensed macrocycle of the formula (IV):

with the compound of the formula R OOC-CHX-(CH2)2-COOR', in which X means a group to delete, such as a halogen atom, preferably bromine, (C1-C3)-Ala is or benzyl,

- implementation of hydrolysis or hydrogenation of the ester functional groups, where R' is different from N

to obtain hexanone acid of formula (V):

- then in the introduction in the interaction of the salt or oxide of complexing with metal hexanone acid to obtain the corresponding chelate or one of its salts with a base;

- and finally, in the introduction into interaction with the chelate in the presence of activating carboxyl functional group agent, an amine of the formula RNH2in which R has the same meaning as in the formula (I), to obtain triamide formula (I).

The acid of formula (V) and its chelates with metals, particularly with gadolinium chelate, and their salts with a base, such as NaOH, which is an intermediate in the synthesis of products of formula (I), constitute another object of the invention.

The invention relates also to contain the compound of formula (I) compositions for obtaining images by magnetic resonance, when M denotes a paramagnetic cation, or for medical radiology, where M means a radioactive element, or to radiology, where M denotes the cation of a heavy atom that absorbs X-rays, moreover, ipirti.

Finally, the invention relates to methods of imaging in medicine, which consist in the introduction of the patient containing the compound of formula (I) composition and observation of the study area, obtained using magnetic resonance, centigray or under the action of X-rays.

Diagnostic compositions according to the invention together with the compound of the formula (I) may contain additives such as antioxidants, buffers, osmolality regulators, stabilizers, salts of calcium, magnesium or zinc, or minor amounts of other chelates with these cations or complex-forming compounds. Examples of preparation of such compositions are General guidelines and especially in Remington's for Pharmaceutical Science, 18th-e edition (1990), Mack. Pub. Su.

Single dose depend on the nature of contrast product, route of administration, as well as from the patient and especially on the nature of the investigated violations. For intravenous injection and monitoring using magnetic resonance solution concentration is 0.001 to 0.5 mol/l and enter in the amount of 0.001-0.1 mmol/kg of body weight of the patient.

Contrast the products according to the invention can be used to visualize the brain, as well as such institutions as the ser is of permeability anomalies, neoplastic, inflammatory, or ischemic abnormalities.

The various stages of the synthesis of compounds according to the invention is carried out in conditions similar to those described in the literature for the reactions of the same type.

The macrocycle of the formula (IV) can be obtained according to the method Richman and Allans described in Inorg. Chem., 32, 5257-5265 (1993).

The substitution of nitrogen atoms is carried out, for example, by influencing complex-popularpage ether in the presence of inorganic or organic bases, such as NaOH, Na2CO3or N(C2H5)3in solution in a polar solvent, such as alcohol, or preferably in an aprotic solvent such as acetonitrile or tetrahydrofuran.

Hydrolysis of the ester groups is carried out by exposure to a base or acid in water or aqueous-alcoholic medium.

Complexation perform classical way, for example as described in U.S. patent 5554748 or in Helv. Chim. Acta, 69,2067-2074 (1986).

To obtain a chelate with gadolinium may be injected into the interaction GdCl3or Gd2ABOUT3with the compound of the formula (V) in aqueous solution at pH value of 5 to 6.5. You can also share osobenno using ion-exchange resin.

The relative percentage of the isomers in the mixture resulting from the presence of three asymmetric carbon atoms can be changed by incubation for several days at temperatures above 80C aqueous solution of the chelate at pH values close to 3.

The amidation reaction can be carried out in aqueous medium, if necessary in the presence of a third solvent, such as dioxane or tetrahydrofuran, with an activating agent such as a soluble carbodiimide, such as carbodiimide containing an amino group described in J. Org. Chem., 21,439-441 (1956) and 26, 2525-2528 (1961) or in U.S. patent 3135748, or Quaternary ammonium group described in Org. Synth., V, 555-558, which include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and 1-cyclohexyl-3-(2-morpholino-ethyl)carbodiimide-p-toolswhat. The reaction can also be carried out with N-hydroxysultaine, as described in Bioconjugate Chem., 5, 565-576 (1994), or 2-succinimido-1,1,3,3-tetramethylethylenediamine and similar compounds described in Tetrahedron Letters, 30.1927-1930 (1989).

Another way is to obtain the intermediate activated complex ether by introducing into the interaction, for example, N-hydroxy-sulfosuccinate can be solubilisation by salt formation with an inorganic cation, for example, a cation of ammonium or of sodium.

When using 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline (EEDQ) reaction can be performed in aqueous-alcoholic medium.

Some of the amines RNH2are known compounds; others receive similar ways, preferably by introduction of the phenyl nuclei gradually, based on the phenyl-containing group, R1- R5and Deputy suitable for education, depending on the need, the groups Z, Z' or Z".

You can also refer to the patents WO-96/09281 or WO-97/01359 in obtaining amines, in which Z denotes CH2CONH, R = q = 0, R1= R3= R5= halogen or H, and R2= R4= CONQ1Q2.

In the case of some aminoalcohols predecessors HNQ1Q2, Q1and/or Q2mean group CH2(CHOH)n(CH2OCH2)r(CHOH)tCH2OH, where t = 0, r = 0,1, n = 0 - 4; they can be obtained

from amerosport or primary alkylamine, which is injected into the interaction with the sugar, followed by the restoration of the obtained imine as described in applications for European patents EP-A-675105 or EP-A-558395;

- or from Bensalem Sogno gidroksilirovanii, then remove the benzyl group by catalytic hydrogenation.

Depending on the configuration entering the reaction of sugar get different stereoisomers.

The aminoalcohols in the case when r = 1, n = t = 0, is obtained from 2-aminoethoxyethanol, which is injected into the interaction with the epoxide or suitable gidroksilirovanii alkylhalogenide or even gidroksilirovanii aliphatic aldehyde, such as monosaccharide, to obtain the imine, then restore catalytic or chemical means.When r = n = 1, aminoalcohols can be obtained by exposure of the epoxide

suitable primary amerosport, and the above-mentioned epoxides obtained by oxidation of the corresponding ethylene derivatives with nagkalat or peroxidizability, as described in J. Org. Chem., 26,659-663 (1961) and 48, 888-890 (1983).

Received these methods aminoalcohols, you can specify alcohols, in which Q1= CH2(SNON)4CH2HE and Q2= Q1or CH2(SNON)CH2HE;

Q1= CH2(SNON)2CH2HE and Q2= CH2SNONCE2O(CH2)2HE or (CH2)2OCH2SNONCE2HE; Q1= CH2 is whether q is different from zero, formed a bridge Z between the two phenyl nuclei, before or after the bridge Z'.

For example, the compound of formula (VI):

can be obtained when Z represents a relationship of diphenylene derivatives of the formula (VII) or their esters:

The compound of formula (VII) in which Z' is O, described in Macromoleculare Chemie, 130. 103-144 (1969); a compound in which Z' is NH, described in Indian J. Chem., 13, 35-37 (1975); a compound in which Z' is CH2or, is described in J. Pharm. Sci., 55 (3), 295-302 (1966); the compound in which Z' represents a relationship described in Synth. Comm., 24 (22), 3307-3313 (1994); and the compound in which Z' is S, described in II Farmaco, 44 (7-8), 683-684 (1989).

Other compounds of formula (VII) can be obtained in a similar way: for example, when Z' means HNCONH by exposure to O2N6H4PSYOPS on H2N6H4COOH in anhydrous environment, or when Z' is NHCO or CONH, by reacting the aromatic carboxylic acid with a suitable aniline in solution in an aprotic solvent such as CH2Cl2WITH6H5CH3CH3SOP(CH3)2or by reacting an aromatic acid with aniline in the presence of the sulfonic acid chloride, treat the dust NO2in the compound of formula (VII) to the NH2can be carried out in a known manner with hydrogen in the presence of a catalyst or by chemical means.

When Z in the formula (VI) means CH2-CONH, glycine, carboxylic group is activated and the group of NH2protected, enter into interaction with the compound of the formula (VI) in which Z represents a relationship, or with aniline containing, if necessary, protected group, the predecessor of Z'.

Glycine protected, for example, in the form of a carbamate, in particular tert-BUTYLCARBAMATE (Synthesis, 48 (1986)) and benzylcarbamoyl (Chem. Ber., 65, 1192 (1932)); in the form of phthalimide (Tetrahedron Letters, 25, 20, 2093-2096 (1984)); using benzyl (Bull. Soc.Chim. Fr., 1012-1015 (1954)), with N-allyl (Tetrahedron Letters, 22, 16, 1483-1486 (1981)) (see also the book by T. W. Greene "Voir aussi Protective Groups in Organic Synthesis", 315-349 (J. Wiley and Sons, Inc.)). The protective group for NH2, fixed at Z, is usually removed only after the introduction of the group R; classically, phthalimido group is removed by exposure to hydrazine, whereas benzyloxycarbonyl or benzyl group is removed by catalytic hydrogenation.

When Z = CH2and Z' = CONH or CONHCH2CONH, 4-aminomethylbenzoic acid, in which the group NH2protected, you can enter in wsas substituted benzoic acid, the carboxyl group of which is blocked by esterification.

When Z is (CH2)2THE N, RN2can be obtained by exposure to an excess of ethylene diamine in a suitable ester of benzoic acid, containing the group-the predecessor of Z', possible protected, or a more complete part of the R.

The compound of formula (VI) after the protection group NH2if activated in the form of a carboxylic acid or with the help of an agent, peptide binding, enter into interaction with the group is the predecessor of Z, which contains the end of the phenyl nucleus, suitable follows substituted with R1- R5to obtain, after removal of the protective group of the amine RNH2.

Conditions for obtaining amines RNH2will be better understood from the following examples. Mass spectra of these products (ionization electron spray) as obtained in the examples of the products correspond to the expected structure.

The compounds a and A': RNH2where

Connection:

(a) 1-Deoxy-1-(2,3-dihydroxypropyl)amino-D-galactic of D-galactose:

Dissolve 35 g of D-galactose in 100 ml of methanol containing 17 g of 3-aminopropanol, and the mixture was kept under stirring n the l of water to effect the hydrogenation of imine at a temperature of 60C. The catalyst is filtered off and the environment are concentrated to a volume of 85 ml of Aminoplast allocate by deposition while adding concentrated solution to 30 ml of isopropanol at a temperature of about 35C.

(b) 5-Amino-2,4,6-Tripolitania acid:

Slowly add 156 g of bromine to 300 ml of an aqueous solution of 50 g of 5-aminoisophthalic acid and 55 ml of 37% hydrochloric acid. After stirring overnight, the excess of bromine is neutralized by adding an aqueous solution of sodium bisulfite, and then precipitate out. Yield: 90%.

(C) 5-(Palmitoylated)-2,4,6-Tripolitania acid:

Slowly add 27 ml of thionyl chloride to a solution of 69 g of N-phthaloylglycine in 200 ml of dimethylacetamide at a temperature of 10C, then after stirring for 2 h at a temperature of 15-20C add 100 g viseporodicnog acid. After keeping overnight at room temperature the mixture was poured into 800 ml of hot water. Thus emit 140 g of the final product.

(d) the acid chloride viseporodicnog acid:

At a temperature of 18 ° C to a solution of 100 g of decollate in 300 ml of dioxane and 50 ml of dimethylformamide is slowly added 70 ml of thionyl chloride. Precipitated after stirring for FYROM. Thus obtain 70 g of solid beige color.

(e) N',N'-Bis(2,3,4,5,6-pentahydroxy)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-tribromo-5-(palmitoylated)isophthalamide:

Dissolve 125 g of amino-Galactica obtained at stage (a), in 610 ml of N-methylpyrrolidone at a temperature of 80 ° C, then at a temperature of 60C add 17 g PA2CO3and 102 g of acid chloride of decollate. After keeping at this temperature for 2 h, the reaction medium is brought to room temperature, then filtered. The filtrate is introduced into 1.5 liters of isopropanol; the precipitation is dissolved in water and subjected to chromatography on ion-exchange resin in the form of H+to remove the original amine. Thus emit 136 g of solid product.

(f) Connection of:

125 g Videolooking phthalimide dissolved in 520 ml of N-methylpyrrolidone and 175 ml of water at a temperature of 70C and add 8 ml of hydrazine hydrate is added, after which the medium was incubated for 2 h at a temperature of 90. The medium was then cooled down to a temperature of 20 ° C, then poured into 1.6 l of ethanol. The precipitation is cleaned by passing the aqueous solution through an ion-exchange resin in the form of H+.

The compound a':

Connection And' can be obtained through the implementation stages b) to f) described above to obtain compounds And, on the basis of amino-glucit obtained in stage a'), or by implementing the next stage e').

(e') is Dissolved 95 g of amino-glucit obtained at stage (a') in 460 ml of dimethylacetamide at a temperature of 90 ° C, then at a temperature of 65S add 32 ml of triethylamine and 117 g of acid chloride of decollate described in stage (d) above when the connection A. After incubation for 4 h 30 min at a temperature of 55-60C reaction medium is brought to room temperature and filtered. The resulting solution at a temperature of 50C slowly poured into an aqueous solution of hydrazine (11 ml 115 ml of water); after incubation for 3 h at a temperature of 80C brought to room temperature, the medium is acidified up to pH 1 by adding 1N. aqueous solution of Hcl. The precipitate was separated and the filtrate with stirring, poured into 3 l of ethanol. The precipitation is dried, then purified by diafiltration to remove the larger part of the molecules with low molecular weight and the resulting solution podvergayutsya. Analysis by high performance liquid chromatography (HPLC) on a column of 2 when using eluent 2: CF3COOH in water, the pH of 3.3/CH3CN.

Connection: RN2where

(a) 4-Phthalimidomethyl acid:

Within 72 hours at the boiling point under reflux withstand a mixture of 10 g of 4-aminometilbensana acid, 14.5 g of carbamaxepine, and 9.2 ml of triethylamine and 140 ml of tetrahydrofuran. The precipitation emit at room temperature; after washing the aqueous acid solution and drying obtain 14.5 g of product. So pl. = S.

(b) the acid chloride viseporodicnog acid:

To a solution of 13.5 g of the acid in 55 ml of dioxane was added 1 g of tricaprylmethyl ammonium chloride (aliquat® 336) and 5.3 ml of thionyl chloride. After stirring for 12 hours at a temperature of 80C Wednesday concentrated to dryness and the remaining solid is washed with diisopropyl ether. Weight is 14 year

(C)2,4,6-Tribromo-5-(phthalimidomethyl)isophthalic acid

In 50 ml of N-methylpyrrolidone dissolve 14 g of carboxylic acid and 15 g of 5-amino-2,4,6-tribromophenol acid and the environment maintained at a temperature of 100C for a few hours. The solution in fact is on the product.

HPLC (high performance liquid chromatography: column No. 1: Symmetry® C18;

100; 5 μm; 1 = 25 cm; d = 4.6 mm, Waters).

Eluent No. 1: 0.005 M solution of CH3NH4/ CH3CN.

Gradient: from 80% to 20% (vol/vol) for 15 min; flow rate = 1 ml/min; retention time (tr) = 4,5 minutes

(d) the acid chloride viseporodicnog acid:

To a solution of 5.5 g of the acid in 40 ml of dioxane is added 5.6 ml of dimethylformamide and 9 ml of thionyl chloride, keeping the temperature below 5C. After 30 min the medium was poured into 150 ml of water and the precipitation emit. Weight = 4,6,

(e) Connection:

2.3 g of the Carboxylic acid contribute to the solution of 4 g of amerosport - 1-deoxy-1-(2,3-dihydroxypropyl)amino-D-Galactica - in 15 ml of N-methylpyrrolidone at a temperature of 65 degree Celsius. After 3 h 30 min add 4 ml of water and the reaction medium is brought to a temperature of 90°C, then add 0.3 ml of hydrazine hydrate is added. After incubation for 2 h at a temperature of 90 solution at room temperature, poured into 80 ml of ethanol. The selected residue is dissolved in 10 ml water and a solution with a pH of 1 purify by chromatography on anion-exchange resin in the form of HE-type Amberlite®then on cation-exchange resin in the form of N+type MAS®
; 100 RP18; 5 μm; l = 25 cm; d - 4 mm; (Merck®).

Eluent No. 2 solution CF3COOH/CH3JV (LV 33) Gradient: from 98 to 77% (volume/volume) for 25 min; flow rate = 1 ml/min; retention time: 18-22 minutes

Connection: RN2where

To a solution of 5.5 g of diisobutylamine in 30 ml of N-methylpyrrolidone at a temperature of 65S add 2.3 g of the carboxylic acid obtained according to the previous stage (d). After incubation for 4 h at a temperature of 65S add 8 ml of water, then at a temperature of 90 ° C add 0.3 ml of hydrazine hydrate is added, and after incubation for 2 h at this temperature, the reaction medium at a temperature of 20 ° C is poured into 130 ml of water. The precipitation was washed with ethanol, then dissolved in 10 ml of water, the solution adjusted to a pH value of 1.5, and then purified by chromatography on anion-exchange and cation-exchange resins. Thus obtained 1.7 g Amin.

HPLC: column No. 2; eluent No. 2; retention time: 18 minutes

Compound D: RNH2where

(a) N,N'-[Bis(2,3,4,5,6-pentahydroxy)]-2,4,6-tribromo-5-(glycylamino)isophthalamide:

1. Dissolve 15 g of dicarbocyanine in 60 ml of N-methylpyrrolidone at a temperature of 80C and Wednesday at tribromoethanol acid. After stirring for 1 h at this temperature and 16 h at room temperature the precipitate is removed and the solution was poured into 160 ml of isopropanol. Selected sediment has a mass of 20 g

2. Hydrazines:

20 g Videolooking product and 1.7 ml of hydrazine hydrate is added bring in 40 ml of water at a temperature of 70C. After stirring for 3 h, acidified up to pH 4 by adding 6N. hydrochloric acid at room temperature. Then remove the precipitated precipitate and the filtrate is neutralized by adding 1N. an aqueous solution of sodium hydroxide. In excess hydrazine is removed by reverse osmosis. The remaining solution is treated with 1 ml of strong cation-exchange resin, then with the help of 6.5 ml of a weak anion exchange resin.

The final product is then extracted from the solution by fixing on a strong cation exchange resin in the form of N+where his elute with water dilute (0.1 M) solution of sodium chloride. Weight = 8,

HPLC: column No. 2; eluent No. 3;

gradient: CF3COOH in water (pH 3,4) / CH3JV from 95 to 50% (volume/volume) for 50 min; flow rate 1 ml/min; retention time: 7 minutes

(b) 4-[4-Nitrobenzamide]benzoic, kikoti 36 ml of dimethylacetamide, keeping the temperature below 25C. After stirring for 24 h at a temperature of 10 ° C add 50 ml of dichloromethane to precipitate the desired product. After washing with water and drying produce 14.5 g of product.

(C) 4-[4-Aminobenzamide]benzoic acid:

A suspension of 13.6 g viseporodicnog acid in 180 ml of water to which was added 24 ml of 1N. an aqueous solution of sodium hydroxide and 1.4 g of 10% palladium-on-charcoal, is exposed to hydrogen pressure of 0.6 MPa for 4 h

The final pH value of the suspension is then adjusted to 10, and then filtered through Celite®to remove the catalyst. Sediment deposited during the acidification of the filtrate to a pH value of 5.3, isolated and dried. Weight = 10.6 g; so pl. > S.

(d) 4-[4-(Palmitoylated)benzamido]benzoic acid:

To a solution of 9 g phthalimidobutyl acid in 40 ml of dimethylacetamide at a temperature of 10 ° C is added dropwise 3.2 ml of thionyl chloride, and then after stirring for 3 h, at temperatures below 20 ° C type of 10.5 g viseporodicnog amino acids.

After stirring for 12 h, the medium was poured into 400 ml of water, and separate the precipitate is washed with hot water. The weight after drying is 18 g; so pl. > add 2.5 ml of thionyl chloride and 1 ml of dimethylformamide and the mixture was kept under stirring at 50C for 5 hours. After adding one volume of isopropyl ether to provide 10 g of sediment.

You can also use the acid in the form of a suspension in toluene with tricaprylmethyammonimum as a catalyst.

(f) N,N'-Bis(2,3,4,5,6-pentahydroxy)-2,4,6-tribromo-5-(4-[4-(palmitoylated)benzamido]benzoylglycine)isophthalamide:

A solution of 2.25 g of the carboxylic acid with 5 g of N,N'-bis(2,4,5,6-pentahydroxy)-2,4,6-tribromo-5-(glycylamino)isophthalamide and 0.7 ml of triethylamine in 25 ml of dimethylacetamide or N-methylpyrrolidone incubated for 12 h with stirring, then poured into 60 ml of ethanol. Thus emit 6.2 g of sediment.

HPLC: column No. 2; eluent No. 3; retention time = 27-35 min (mixture of isomers).

(g) Hydrazines:

A solution of 0.6 ml of hydrazine hydrate is added in 10 ml of water are added to a solution of 10 g videolooking phthalimide in 40 ml of dimethylacetamide at a temperature of 80C. After stirring for 3 h at this temperature, the cooled mixture was poured into 125 ml of ethanol. Allocate 9 g of residue which is cleaned by treating its aqueous solution using a strong anion exchange resin (HE-), then a weak cation exchange resin (H+). Weight = 8,

You can also p is znachitelnoi molecular weight by ultrafiltration, then perform the final deposition in aqueous ethanol.

HPLC: column No. 2; eluent No. 3, but in a ratio of 90/10 (vol/vol) with elution in isocrates mode at a flow rate of 1 ml/min; retention time = 28-35 minutes

Compound E: RNH2, where

(a) 5-(4-Nitrobenzamide)-2,4,6-Tripolitania acid:

For 18 h at the boiling point under reflux withstand 50 g of acid chloride of p-nitrobenzoic acid and 75 g of 5-amino-2,4,6-tribromophenol acid in 400 ml of dioxane. After cooling, the precipitate is filtered off, washed with 50 ml of dioxane and dried. Weight = 115,

(b) 5-(4-Aminobenzamide)-2,4,6-Tripolitania acid:

A solution of 180 g videolooking nitro-derivatives in 600 ml of water adjusted to pH 6 by adding 5N. an aqueous solution of sodium hydroxide and hydronaut at a pressure of 5105PA in the presence of PT type 156 (Johnson Matthey) within 7 hours the Catalyst is filtered off and the water is evaporated under reduced pressure. Weight = 80, HPLC: column No. 2; eluent No. 4: CF3COOH in water (pH of 2.8) with methanol (99/1 ratio by volume); flow rate: 1 ml/min; retention time: 3.6V min (18,8 min for nitrocompounds).

(C)5-(4-[4-Phthalimidomethyl)be the of arbetareparti and 9.2 ml of triethylamine in 140 ml of tetrahydrofuran maintained at its boiling temperature for 72 hours The precipitate separated from the reaction medium by filtration at room temperature, washed with diethyl ether and 1N. aqueous solution of hydrochloric acid. Obtain 14.5 g of a solid substance, 12.2 g of which is at a temperature of 10C dissolved in 90 ml of N,N-dimethylacetamide and 3.5 ml of thionyl chloride; after stirring for 3 h in the environment contribute to 23.4 g obtained at the previous stage of aniline and stirred for one night, after which the mixture was poured into 900 ml of water. Isolated and washed with water the precipitate is recrystallized from 200 ml of dioxane. Weight = 30,

HPLC: column No. 2; eluent: 0.1 M solution of CF3COOH in water/CH3CM ( in a ratio of 90/10 by volume) gradient after 20 min, up to 40/60 over 30 min; flow: 1 ml/min; retention time = 26-29 minutes

(d) Dichlorohydrin acid:

30,3 g Obtained in the previous phase derivative of isophthalic acid are dissolved in 150 ml of dioxane containing 26 ml of dimethylformamide, and at a temperature of 5 ° C is added dropwise 42 ml of thionyl chloride. After keeping at the temperature of 0C for 30 min the mixture was poured into 550 ml of water and precipitated precipitate is filtered off, washed with water and diisopropyl ether. Weight = 26 g after drying.

(e)N,N'-Blamed:

1. 10 g of Dichlorohydrin acid are added to a solution of 15 g of 1-deoxy-1-(2,3-dihydroxypropyl)amino-D-Galactica in 100 ml of N-methylpyrrolidone at a temperature of 60C. After stirring for 4 h at this temperature, the medium is brought to room temperature, poured into 1 l of isopropanol. Precipitated precipitate is isolated and dried.

HPLC: column No. 2; eluent No. 5: 0.01 M solution of CH3NH4in the water/CH3SP; gradient from 85 to 50% (vol/vol) for 20 min; flow rate: 1 ml/min; retention time = 16 minutes

2. Remove phthalimide group:

20,4 g Videolooking solids with stirring and at a temperature of 80C bring in 80 ml of N,N'-dimethylacetamide, and then add 1.6 ml of hydrazine hydrate is added in the form of a solution in 20 ml of water. After incubation for 3 h at this temperature, the reaction medium at room temperature, poured into 1 l of ethanol. The precipitation produce, dried, then dissolved in 40 ml of water. At a temperature Of°C add about 2 ml of 6N. aqueous HCl to reduce the pH to 2; the medium is filtered through celite®are then cleaned by passing through the ion-exchange resin (anionic Amberlit®and cationic MAS®). Get then 6 g of the desired Pro/P>

(a) At a temperature of 120C 50 g of 1-deoxy-1-(2,3-dihydroxypropyl)amino-D-Galactica dissolved in 300 ml of dimethylacetamide, and then at a temperature of 80C quickly add 38 g of acid chloride of 5-(palmitoylated)-2,4,6-triiodoisophthalic acid (obtained according to U.S. patent 4283381) and 17 ml of triethylamine. After stirring for 5 h at 80°C medium filtered at room temperature and the filtrate is poured into 800 ml of isopropyl alcohol and the precipitate is isolated and dried.

The excess of the original amerosport removed by chromatography of an aqueous solution of this residue on the ion-exchange resin in the form of+.

Exercise hydrazines phthalimide group in the aquatic environment for N,N'-[(2,3,4,5,6-pentahydroxy)(2,3-dihydroxypropyl)]-2,4,6-tried-5-glycosaminoglycan.

(b) To 70 g obtained in stage (a) amine in the form of a solution in 200 ml of dimethylacetamide add 23 g of acid chloride of 5-(palmitoylated)-2,4,6-triiodoisophthalic acid and 12 ml of triethylamine. After stirring for 24 h at room temperature, the reaction medium is then poured into 1500 ml of isopropyl alcohol and allocate the precipitation.

Thus, the obtained crude phthalimide in the form of a solution in 1 and 65/35 by volume). The removal of the protective group from the amino group of phthalimide carried out by hydrazinolysis: 57 g phthalimide treated with 3 ml of NH2-NH2in 200 ml of water at a temperature of 80C; after 3 h falicitated precipitated at pH 1 and the filtrate is evaporated, receiving the oil, which is purified by precipitation from ethanol and chromatography was carried out on the anion exchange resin and a weakly basic Amberlite®) and cation exchange resin (MAS NR company Rohm and s).

Analytical HPLC: column No. 2; eluent No. 8: H2O/CH3SP; gradient from 95 to 80% within 45 min; retention time: 33-49 minutes

In the same conditions obtained in stage (a) amine retention time is 6 to 16 minutes

You can get a different mixture of isomers of compounds of F when applying the above method to the 1-deoxy-1-(2,3-dihydroxypropyl)amino-D-glucit. Analytical HPLC: column No. 2; eluent No. 8.

The corresponding product obtained in stage (a): retention time = 7-24 min; the final product: retention time = 30-40 minutes

Below, as an illustration describes how to obtain some of the chelates according to the invention.

Example 1

3,6,9,15-Tetraazabicyclo[9,3,1]pentadec-1(15), 11,13-triene-3,6,9-three(b-glutaric)1]pentadec-1(15),11,13-the triens in 570 ml of acetonitrile and at a temperature of 80C added 34 g PA2CO3gradually 77 g of methyl-Brahmputra in the form of a solution in 110 ml of acetonitrile. After keeping the environment within 24 h at its boiling point under reflux it is filtered at a temperature of about 20C and the filtrate is evaporated to dryness. The remaining solid is purified by chromatography on silica, elwira a mixture of ethyl acetate / heptane (in a ratio of 6/4 by volume). Weight = 25,

2. Hydrolysis

For 3 days at a temperature of 70C withstand 5.8 g obtained at the previous stage of the product in 15 ml of methanol, to which was added 42 ml of 5N. an aqueous solution of sodium hydroxide. After adding 100 ml of water, the pH value of the solution was adjusted to 6.5 by adding a cation-exchange resin (H+), then after filtering, the solution is injected into contact with the anion exchange resin in the form of HE-. Product release from the resin using a mixture of acetic acid / water (50/50 by volume).

HPLC: column No. 2; eluent No. 6: 0,037 N. a solution of H2SO4in the water /CH3SP; gradient from 100% to 20% (volume/volume) for 50 min; flow rate 1 ml/min, retention time = 12,5 - 13,5 min (several peaks).

3. Complexation:

3 g of the Acid and 1.9 GN. an aqueous solution of sodium hydroxide. After incubation for 3 h at a temperature of 60C environment is filtered at a temperature of 20 ° C, then poured into 100 ml of ethanol. Allocate sodium salt complex with the release of 70%.

HPLC: column No. 2; eluent No. 6; retention time = 15-16 min (several peaks).

Example 2

The compound of formula (I), where

In 10 ml of water injected 0.5 g obtained in example 1 complex and 3.15 g of amine RNH2. The pH value was adjusted to 6 by adding 0.1 G. of an aqueous solution of sodium hydroxide, after add 2 equivalent hydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI). After incubation for 3 h at a temperature of 40 ° C the medium was poured into 100 ml of ethanol and the precipitate isolated.

Purification is carried out by ultrafiltration of an aqueous solution of compounds through the membrane of polyethersulfone, with a threshold gap 3 KDa, followed by chromatography on a column with silanation the silicon dioxide LiChroprep®(standard mixture RP2 and R18 (50/50)) Merck, elwira a mixture of water / CH3JV (gradient from 98% to 95%). Weight = 0,8,

HPLC: column No. 2; eluent No. 7: H2O / CH3SP; gradient from 98 to 70% (vol/vol) for 20 min; the flow">

A) Derived galactose

of 8.3 g of Compound a and 1.8 g obtained in example 1 complex is dissolved in 100 ml of water. After adjusting the pH to 6 by adding 1N. aqueous solution of Hcl added 2.7 g DI and 150 mg of sodium salt of (N-hydroxysuccinimidyl)-3-sulphonic acids (NHS). After stirring for 2 h the solution was poured into 300 ml of ethanol and precipitated precipitate out. It can be purified by preparative HPLC on Lichrospher®18-100E - 12 µm (Merck) or by ultrafiltration. Analytical HPLC: column No. 2; eluent No. 7; retention time = 12 minutes

A') Derived glucose:

By interacting compounds And' with that obtained in example 1 complex, in the same working conditions as in case A, get crude compound corresponding to the formula (I). It can be purified by chromatography on a column Purospher®RP18, elwira a mixture of N2O/CH3The JV. Yield: 40%.

Example 4

The compound of formula (I), where

2.5 g Obtained according to example 1 of the complex and 11 g of compound dissolved In 60 ml of water; after adding 1N. aqueous solution of Hcl until pH 6 add 45 ml Aceto is the atur about 20C, leading from time to time the pH to 6 by adding 1N. an aqueous solution of sodium hydroxide. The solution is poured into 500 ml of ethanol and separate the precipitate dried. Weight is 11.7 g

The product was then purified by preparative chromatography under pressure on a column Lichrospher®With 18-10 μm; 1=25 cm, d = 50 mm (Merck), elwira a mixture of water / acetonitrile with a gradient from 95 to 90% over 20 min, then 85% for 25 min; flow 80 ml/min Yield = 45%.

Analytical HPLC: column No. 2; eluent No. 8: H2O/CH3SP; gradient from 95 to 80% within 45 min; retention time = 31 min

Example 5

The compound of formula (I), where

receive according to the method described in example 4, but using the connection With.

Analytical HPLC: column No. 2; eluent No. 8; retention time = 25-29 minutes

Example 6

The compound of formula (I), where

1.6 g Obtained according to example 1 of the complex and 7 g Amin F dissolved in 40 ml of water. When the pH value is 7, add 0.3 g of NEWT and 1.5 g of EDCI, then 30 ml of acetone. The medium is stirred for 4 hours, maintaining the pH value of about 6. The precipitate obtained by pouring the solution in 450 ml of ethanol, cleaned the PMA Merck); elwira a mixture of water / acetonitrile (gradient from 90 to 80%) within 5 min); flow rate = 80 ml/min

Analytical HPLC: column No. 3: Purospher®; R18 blocked with residual silylene groups; 5 μm; L = 250 mm, d = 4 mm; (Merck); eluent No. 7, but the gradient from 85% to 70% within 10 min (volume/volume) after 20 min; retention time = 29 minutes

Example 7

The compound of formula (I), where

The product is obtained when applying the method described in the previous examples, when using amine D.

Analytical HPLC: column No. 4: Bond®V - C18; 1=250 mm, d = 4 mm (Hewlett®Packard; eluent No. 1, but the gradient from 90 to 82% within 60 min; retention time = 42-49 minutes

Example 8

The compound of formula (I), where

The product is obtained when using amidation conditions similar to those in the previous examples.

Analytical HPLC: column No. 2; eluent No. 7, but the gradient from 98% to 85% within 40 min; retention time = 24 minutes

Example 9

The compound of formula (I), where

Analytical HPLC: column No. 2; eluent: H2O/CH3JV in a ratio of 95/5 by volume, then after 20 min gradient for dostizheniya formula (I), where

receive by entering into interaction connection F with the complex of example 1:

1 g of the Complex and 12 g Amin R dissolved in 200 ml of water and the pH adjusted to 6 by adding 6N. aqueous solution of Hcl. Then add 0.1 g of EDCI and 0.25 g NOWT; the environment is maintained with stirring for 48 hours, maintaining the pH value equal to 6 by adding a 2% aqueous solution Panso3. The final crude product is produce by introducing environment in 10 volumes of ethanol and purified by preparative chromatography on a column Purospher®; RP18, 10 μm; 120 (Merck), elwira a mixture of N2O/CH3The JV. Yield: 30%.

Analytical HPLC: column No. 2 - eluent No. 8; retention time = 12 minutes

1. Chelate metal with the compound of the formula (I)

in which R denotes a group of formula (II)

Z indicates the bond or group selected from the groups CH2CH2-CO-NH or (CH2)2-NH-CO;

Z’ is a bond or a group selected from the groups O, S, NQ, CH2WITH, CO-NQ, NQ-CO., NQ-CO-NQ, CO-NQ-CH2-CO-NQ;

Z” means the bond or group selected from the groups CO-NQ, NQ-CO, CO-NQ-CH2-CO-NQ;

p and q denote integers whose sum is from 0 to 3;< CO-NQ1Q2and NQ1-CO-Q2and Q1and Q2identical or different, denote H or (C1-C6)-alkyl, possibly interrupted by an atom or atoms of oxygen and at least one of the radicals R1-R5means aminogroup or R1, R3and R5independently of one another denote H, Br, Cl or I and R2and R4the same, means a group of the formula (III)

where Z’” means a group selected from the groups CO-NQ, CO-NQ-CH2-CO-NQ, CO-NQ-CH2, CO-NQ-(CH2)2-NQ-CO and NQ-CO-NQ;

R’1, R’3and R’5identical or different, denote H, Br, Cl or I;

Q’1and Q’2identical or different, denote H or (C1-C6)-alkyl, possibly interrupted by an atom or atoms of oxygen;

Q denotes H or (C1-C4)-alkyl,

provided that the alkyl group may be optionally mono - or polyhydroxyalkane.

2. Chelate under item 1, which are compounds of formula (I) in which p and q mean 0 and R2and R4mean CO-NQ1Q2.

3. Chelate under item 1, which are compounds of formula (I), in which the sum of p + q is not 0 and R2and R4not mean is equal to 1 or 2 and R2and R4not mean a group of the formula (III).

5. Chelate under item 1, which are compounds of formula (I), in which groups R1- R5at the same phenyl nucleus together contain 6-20 groups HE.

6. The chelate according to any one of paragraphs.1-5, which are compounds of formula (I) in which any present group CONQ1Q2or, optional, group CONQ’1Q’2contains 6-10 groups HE.

7. The chelate according to any one of paragraphs.1-6, which are compounds of formula (I) in which R1, R3and R5are the same and are selected from Br and I, and in which R’1, R’3and R’5when they are present, are identical and are selected from Br and I.

8. The chelate according to any one of paragraphs.1-7, which are compounds of formula (I) in which Z denotes CH2or CH2-CO-NH, Z’ represents a group chosen among CO-NH, CO-NH-CH2-CO-NH, NH-CO-NH, and Z stands for a group selected among CO-NH and-NH-CH2-CO-NH, and the group Z’”, when it is present, means CO-NH or CO-NH-CH2-CO-NH.

9. The chelate according to any one of paragraphs.1-8, which are compounds of formula (I) in which R2and R4mean CONQ1Q2, Q1and Q2mean (C2-When bringing a compound of formula (I), in which Z denotes CH2or CH2-CO-NH, Z’ and Z” are selected from CO-NH, and CO-NH-CH2-CO-NH, p and q are equal to 1 and R2and R4mean CONQ1Q2.

11. Chelate under item 1, which are compounds of formula (I) in which p=q=0; Z=CH2CONH;

R1=R3=R5=Br; R2=R4=CON(CH2(CHOH)4CH2OH)2or

12. Chelate under item 1, which are compounds of formula (I) in which R=1,2; q = 0; Z=CH2; Z’ = CONH; R1=R3=R5=Br; R2=R4=CON(CH2(CHOH)4CH2OH)2or

CON-CH2(CHOH)4CH2HE

CH2-CHOH-CH2OH.

13. Chelate under item 1, which are compounds of formula (I) in which p=q=1; Z=CH2CONH;

Z’=CONH; Z=CONH-CH2CONH; R1=R3=R5=Br; R2=R4=CON(CH2(CHOH)4CH2OH)2.

14. Chelate under item 1, which are compounds of formula (I) in which p=q=0; Z=CH2CONH; R1=R3=R5=Br; R2=R4=

Q’1=Q’2=CH2(CHOH)4CH2OH or Q’1=CH2(CHOH)4CH2OH and Q’2=CH2-CHOH-CH2OH.

15. Chelate under item 1, representing with the R5are the same and are selected from Br and I.

16. The chelate according to any one of paragraphs.1-15, which are compounds of formula (I) with Gd3+or MP2+.

17. Chelate metal with the compound of the formula

and its salts with inorganic or organic base.

18. Chelate under item 17 in which the metal is Gd.

19. The method of obtaining the compounds of formula (I) under item 1, which includes the introduction in the interaction between the macrocycle of the formula

with the compound of the formula R OOC-CHX-(CH2)2-COOR’, where x is the removed group and R’ represents H or (C1-C3)-alkyl, and in the implementation of the hydrolysis of ester functional groups, where R’ is different from H, followed by introduction into the interaction of the salt or oxide of the metal used for the chelate formed product or one of its salts with a base and an introduction to the interaction of the chelate with the amine RNH2in the presence of an agent activating the carboxyl group.

20. Composition for image acquisition in the diagnosis, comprising the chelate according to any one of paragraphs.1-16 with pharmaceutically acceptable excipients and, if necessary, usual to obtain formulations of additives is I chelate according to any one of paragraphs.1-16, in which the metal is gadolinium.

 

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