EP0745064A1

EP0745064A1 - 4,4-disubstituted piperidine derivatives useful as four-pointed ligands for complexing nuclides in nuclear medicine

Info

Publication number: EP0745064A1
Application number: EP95908934A
Authority: EP
Inventors: Wolfgang Brandau; Samuel Samnick
Original assignee: CIS Bio International SA
Current assignee: CIS Bio International SA
Priority date: 1994-02-18
Filing date: 1995-02-13
Publication date: 1996-12-04
Also published as: DE4405140A1; WO1995022527A1

Abstract

Complexing agents for nuclides used in nuclear medicine are disclosed, as well as a process for preparing these complexes and diagnosing agents containing the complexes (I) and their complexes, in particular with Tc-99m. These compounds are used as non-invasive, functional in vivo diagnosing agents in nuclear medicine.

Description

description

4, 4-DISUBSTITUTED PIPERIDE DERIVATIVES AS FOUR-TEETH LIGANDS FOR

COMPLEXING NUCLIDES IN NUCLEAR MEDICINE

The invention relates to new compounds for the non-invasive functional invivo

Diagnostics of various human receptor systems with nuclear medicine

Methods.

The successful treatment of human diseases sets the exact one

Diagnosis of the existing disease process in advance. Imaging procedures often play an outstanding role in this, since they do not involve surgical procedures

Intervention that otherwise not visible organs can be shown.

The methods currently used are divided into two groups. On the one hand there are the processes with which space-demanding processes are mapped. These include in particular X-ray, ultrasound and computer tomography (CT). The NMR diagnosis based on the resonance of atomic nuclei in the magnetic field can also be classified here.

On the other hand there are the nuclear medical procedures, in which after injection of a preparation labeled with a radioactive nuclide, the radiation emanating from the nuclide is registered with a special camera (γ-camera) and converted into an image via a mathematical evaluation. Since in this case preparations are applied that participate in the metabolism of the organism in question, the image obtained reflects the physiological state. In the case of many diseases, abnormal behavior can be detected much earlier than would be the result of a change in the morphological structure. The methods are therefore characterized by the possibility of early diagnosis and a visual description of the functional state of the concerned organs.

Since NMR diagnostics work with contrast agents based on certain nuclides (preferably gadolinium), under certain circumstances this method is also able to make physiological statements.

The nuclides that can be used in nuclear medicine or NMR diagnostics must meet narrowly defined criteria, among other things with regard to the type of radiation and the physical half-life. Depending on the particular question, the following nuclides are used: ^{1 1} C, ¹³ N, ¹⁵ O, ¹⁸ F, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ⁷⁵ Br, ⁷⁷ Br, ^99m Tc, ⁶⁸ Ga, ⁶⁷ Ga, ^{1 1 1} In, ^{1 13m} In, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁶² Cu, ⁶⁴ Cu, ⁶⁷ Cu, ¹⁵³ Gd or other stable gadolinium isotopes.

The isotopes iodine-123 and technetium-99m are of outstanding importance in nuclear medicine. Due to their favorable physical half-lives ( ^99m Tc: 6.02 h, ¹²³ I: 13.3 h) and their optimal γ energies ( ^99m Tc: 140 keV, ¹²³ I: 1 59 keV) they have in single photon emission tomography (single photon Emission Tomography, SPECT) found the most widespread.

However, the application of the Technetium-99m available from the ⁹⁹ Mo / ^99m Tc generator, which is chemically present as pertechnetate, does not meet all the requirements of nuclear medicine diagnostics, since only a few human organs can be examined. By complexing with a suitable ligand, however, completely different compounds are obtained in the action. In search of radiopharmaceuticals that have an organ-specific effect, a number of complexing agents for radioactive nuclides, in particular for technetium-99m, have been developed in recent years, which enable

Synthesize complexes with a sufficiently high in vivo stability.

As before, there are still a number of questions for which optimal preparations are not yet available. This includes in particular the pictorial Representation of metabolic processes and receptor systems of the human organism using technetium-containing radiopharmaceuticals. The progress made in the field of technetium radiopharmaceuticals has been summarized by AM Verbruggen (Eur. J. Nucl. Med. 17, 346-364 (1990).

In addition, complexes with ethylene cysteine from WO 90/05733, with

Mercaptoacetyltriglycin from EP-A-0, 1250,013, EP-A-0,427,360, EP-A-0, 173,424 and US-A-4,883,862, with diamidodithiolates from EP-A-0.200,492 and EP-A-0, 135.1 60 and with bisaminodithiols from WO 89/10759, EP-A-0.200.21 1, WO 89/10758, EP-A-0.279.417, EP-A-0.322.876, EP-A-0.344.724, EP-A-0, 163, 1 19 and EP-A-0 381 713 (WO 89/10759) and diaminomercapto (thio) ethers are known from EP-A-0 542 21 6.

By using positron-emitting nuclides of the body's own elements, preferably ^{1 1} C, ¹³ N, and ^{1 5} O, it is possible to represent metabolic processes in vivo without the disturbing influence of a foreign nuclide.

The isotope ¹⁸ F can also be added, which is not a structural element in organic compounds, but is often used there as a hydrogen substituent without significantly influencing its chemical and physiological-chemical properties. The wide distribution of positrons

Emission tomography (PET) is limited by a short physical half-life of the positron emitters (2 min - 1, 8h). Because of this short half-life, rapid synthesis sequences are carried out for the synthesis of PET radiopharmaceuticals, which are preferably carried out as a step-by-step labeling reaction, starting from a suitable precursor molecule.

In the past ten years, various PET radiopharmaceuticals have been developed, in particular for the diagnosis of neurological and myocardial diseases. Advances in the field of PET radiopharmaceuticals have been reported by M. Diksic and RC Reba. "Radiopharmaceuticals and brain pathology studied with PET and SPECT ", CRC Press, Boca Raton, Florida, 1991. However, problems still exist in providing suitable complexing agents for rapid labeling.

The object of the invention was therefore to provide suitable chelating substances for the production of radioactive metal complexes. In particular, the radioactive isotope or the complexing agent should replace isosteric groups in molecules with known biological activity, and should not be additionally introduced into these molecules.

The problem is solved by providing compounds of the general formula I which are suitable as complexing agents

in which RH, - (CHR ₇ ) _a -CH ₂ R ₇ , - (CH ₂ ) _a -C ₆ H ₄ -R ₇ , - (CH ₂ ) _a -C (C ₆ H ₄ -R ₇ ) ₃ , - ( CH ₂ ) _b - (CO) - C ₆ H ₄ R ₇ , - (CHR ₇ ) _a - (CO) -R ₇ , - (CH ₂ ) _b -CH (OH) -C ₆ H ₄ R ₇ , - (CH ₂ ) _b -C (OH) (C ₆ H ₄ - R ₇ ) ₂ , - (CH ₂ ) _b -C (OCH ₂ ) ₂ -C ₆ H ₄ R ₇ , - (CH ₂ ) _a -CH (C ₆ H ₄ -R ₇ ) ₂ , - (CH ₂ ) _b -C (OCH ₂ ) ₃ -

W, X, Y and Z independently of one another denote N or S,

R ₁ and R ₂ together each represent double-bonded O or S and / or

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R _{7 are the} same or different and

H, - (CH ₂ ) _a -CH ₃ , -COOR ', -CONR'R ", OR', SO ₃ R ', -OCOR', -SO ₂ NR'R", - CONHCH ₂ COOH, -SR ' , -NR'R ", -COR ', F, Cl, Br, or I, where

R 'and R "are the same or different and

H, - (CH ₂ ) _b CH ₃ , phenyl, p-hydroxyphenyl, N-piperidinyl, N-piperazinyl or N-morpholinyl,

R _{7 is} also a 5- or 6-membered heterocycle with 1 to 3

Heteroatoms from the series N, S or O means

VH, -COCH ₃ , -COC ₆ H ₅ , -CH ₂ NHCOCH ₃ , -CH ₂ C ₆ H ₅ , -COCH ₂ OH

Means -COCH ₂ COOH or another suitable sulfur protecting group and

m, n and o are each independently 0, 1 or 2 and

a and b each independently represent an integer from 0 to 20, preferably from 0 to 10

mean.

Preferred compounds of formula I are those in which

RH, - (CH ₂ ) _a -C ₆ H ₄ R ₇ , - (CH ₂ ) _b - (CO) -C ₆ H ₄ R ₇ or - (CH ₂ ) _b -CH (OH) -

Y and ZS, preferably together form a disulfide bridge, X and WN is

R ₁ and R ₂ together represent a double bonded oxygen

and or

-H, - (CH ₂ ) _a CH ₃ , -COOR ', -CONR'R ", -NR'R" or -OR', where R 'and R "are the same or different and H, - (CH ₂ ) _{b is} CH ₃ , phenyl or p-hydroxyphenyl,

V denotes -H, -COCH ₃ , -COC ₆ H ₅ or -CH ₂ -C ₆ H ₅ ,

R _{7 is} also a 5- or 6-membered heterocycle and 1 to 3

Heteroatoms from the series N, S or O means, m, n, o and p are identical and 0, 1 or 2 and

a and b are identical and represent an integer from 0 to 5.

Very particularly preferred compounds of the formula I are those in which m, n and o are identical and are 0 or 1, preferably 0. In this case, R ₁ and R _{2 are} each hydrogen or R ₁ and R ₂ together form a double bonded O, provided that with the adjacent X or W a carbonylamido structure

is trained

R ₃ and R _{4 are} - (CH ₂ ) _a -CH ₃ , where a is an integer from 0 to 5 and

R ₅ and R ₆ independently of one another are hydrogen or - (CH ₂ ) _a -CH ₃ , where a is an integer from 0 to 5. The complexing agents of this invention are particularly suitable for forming stable complexes with the following central ^{atoms 99m} Tc, ⁶⁸ Ga, ^{1 1 1} In, ¹²³ In, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁶⁷ Cu, ¹⁵³ Gd or stable gadolinium isotopes. Are particularly preferred

Complexes with ^99m Tc. The complexes are also the subject of this invention.

By varying the central atom and the substitution pattern of the

Complexing agents according to the general formula I are accessible complexes which are particularly well suited for the representation of various human receptor systems.

The complexes according to the invention correspond to the following general formula

II:

in which

R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , V, W, X, Y, Z, m, n and o have the meanings given for the compounds of the general formula I and M ^99m Tc, ⁶⁸ Ga, ^{1 1 1} In, ^{1 13} In, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁶⁷ Cu, ⁶⁴ Cu, ⁶² Cu, ¹⁵³ Gd or a stable gadolinium isotope,

U and T together or independently of each other double bonded O or

S, triple-bonded N, -PKL or H ₂ O, CH ₃ CH ₂ OH, CH ₃ OH, Cl, Br or I means, where

K and L are -OR ', -H, - (CH ₂ ) _b CH ₃ , - (CH ₂ ) _a -O- (CH ₂ ) _b -CH ₃ , where R' is the for

Compounds of the general formula I mentioned and a and b are independently 0 to 10,

p and q are independently 0 or 1.

U and T are preferably either O, N or S, where p and q each represent 1, p 1 and q 0, or p and q 0.

The complexing agents according to the invention can be provided for complex formation in free form or with a protective group on Y and / or Z known to the person skilled in the art. Before or during the complexation reaction, these protective groups are removed by methods known to the person skilled in the art.

The invention further relates to a process for the preparation of the complexes of the general formula II by reacting a complexing agent of the general formula I with metal compounds of the metals M.

The invention further relates to the use of a compound of the general formula II as a non-invasive functional in vivo diagnostic in the

Nuclear medicine. Finally, the invention relates to a diagnostic agent containing a compound of general formula II for use in nuclear medicine.

The synthesis of the complexing agents starts from generally accessible starting materials, which are converted into the desired end products by suitable reaction sequences.

The starting materials used are, for example, 1-benzylpiperidine-4-one or 1- [2'-propyl-2 '- (4 "-fluorophenyl) -1', 3'-dioxolane] -4-piperidone (compound E). Scheme 1 shows the synthesis of a complexing agent starting from one of these starting materials.

The exact reaction sequence is described in Example 1.

example 1

Synthesis of 1-benzyl-4- (2-mercapto-2-methyl-4-aza-pentyl) -4- (2-mercapto -2-methyl-propylamino) piperidine (D).

Preparation of 1-benzyl-4-cyano-4-amino-piperidine (A).

A solution of 8.25 g (0.125 mol) of KCN, 6.95 g (0.125 mol) of NH ₄ Cl and 35 ml of H ₂ O was mixed with 21.79 g (0.1 1 5 mol) of 1-benzyl-4-piperidone in 1 5 ml

anhydrous ethanol dissolved, added and stirred at 23 ° C for 48 hours. The

Crude product was extracted with dichloromethane (3 × 1 50 ml), the combined organic extracts washed with water, dried over Na ₂ SO ₄ , filtered and evaporated to dryness in vacuo. The residue was then

purified chromatographically on silica gel (CH ₂ Cl ₂ / MeOH 9: 1). 25.60 g (95%) of the aminonitrile (A) could be isolated.

IR [cm ^-1 ]: 3300 (NH ₂ ), 3090, 3050, 1 590 (Ph), 2260 (CN).

¹ H-NMR (CD ₂ Cl ₂ , ppm): 7.30 (m, 5H, ArH), 3.50 (s, 2H, CH ₂ -Ph), 2.8-1 .73 (m, 8H, CH ₂ ), 1. 80 (s, 2H, NH _2).

Preparation of 1-benzyl-4-aminomethyl-4-aminopiperidine (B).

5 g (23.22 mmol) of compound (A) were dissolved in 100 ml of methanol and 10 ml of 5 N ethanolic HCl were added. After adding 5 g of PdO / C (10%) as a catalyst, the mixture was hydrogenated at RT (p = 1.1 bar). After the calculated amount of H _{2 had been} consumed, the catalyst was filtered off, the solvent was evaporated in vacuo, the solid residue was treated with MeOH and filtered off. 5.2 g (77.2%) of compound (B) were obtained as the hydrochloride.

IR [cm ^-1 ]: 3150, 1950 ( ⁺ NH ₃ ), 3080, 1580 (Ph), 2900-2810 (CH ₃ , CH ₂ ).

1 H-NMR (free diamine, CDCl ₃ , ppm): 7.28 (m, 5H, Ar.H), 3.50 (s, 2H, CH ₂ -Ph), 2.65 (s, 2H, NH ₂ ), 2.40 (m , 4H, CH ₂ ), 1.60 (m, 6H, CH ₂ ), 1.30 (s, 2H, NH ₂ ). Preparation of 13-benzyl-3,3,6,6-tetramethyl-4,5-dithia-1, 8, 13-triazaspiro

[9,10] pentadecane (C).

To a solution of 1.12 g (5.38 mmol) of 2,2'-dithio-bis (2-methylpropanal) in 20 ml of absolute ethanol was added 1.18 g (5.38 mmol) of compound B (free amine) and for 60 min at 40 ° C touched. The solvent was removed in vacuo, the orange oil dissolved in 30 ml EtOH and slowly added dropwise to a suspension of 2 g (5.3 mmol) NaBH ₄ in 30 ml EtOH. After 24 hours at 40 ° C, diluted with 15 ml of water and extracted with dichloromethane. The combined organic extracts were washed with water, dried over Na ₂ SO ₄ , filtered and evaporated to dryness in vacuo. The residue was

including purified by chromatography on silica gel (CH ₂ Cl ₂ / MeOH 9: 1) and gave 1.58 g (63%) of compound (C).

IR [cm ^-1 ]: 3330 (NH), 3100, 1590 (Ph), 2900-2830 (CH ₃ , CH ₂ ).

1H-NMR (CDCI ₃ ): δ = 7.30 (m, 5H, aromatic H), 3.95 - 3.10 (m, 4H, CH ₂ ), 3.55 (s, 2H, CH ₂ -Ph), 2.90 - 2.30 (m , 6H, NH, CH ₂ ), 2.20 (m, 2H, CH ₂ ), 1.85 (m., 2H, CH ₂ ), 1.60 (m, 2H, CH ₂ ), 1.30 (m, 12H, CH ₃ ).

Preparation of 1-benzyl-4- (2-mercapto-2-methyl-4-aza-pentyl) -4- (2-mercapto -2-methyl-propylamino) -piperidine (D)

2.50 g (6.30 mmol) of compound C was dissolved in 5 ml THF and slowly added under N ₂ to 10 ml of a solution of LiAIH ₄ in THF (0.5 N) at 0 ° C. After 60 minutes under reflux, excess hydride was destroyed by slowly adding 0.1 N HCl while cooling and the pH of the mixture was adjusted to 10 by adding 0.1 N NaOH. The product was extracted with (Et) ₂ O, the combined organic phases washed with water, dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was taken up in 5 ml of absolute methanol and HCl gas was introduced at 0 ° C. 1.83 g (73%) of the hydrochloride of compound D could be isolated. IR [cm ' ¹ ]: 3300 (NH), 3080, 1590 (Ph), 2900-2830 (CH ₃ , CH ₂ ), 2550 (SH).

1H-NMR (CDCl ₃ , ppm) (free base): 7.30 (m, 5H, ArH), 3.60 (s, 2H, H ₂ C-Ph), 3.10-2.90 (m, 4H, CH ₂ ), 2.80 (m, 4H, CH ₂ ), 2.60 (m, 6H, NCH2), 2.00 (s, 4H, NH, SH), 1.37 (m, 12H, CH ₃ ).

Scheme 2

Scheme 2 represents another complexing agent. Details on the synthesis of 1- [3- (4-fluorobenzoyl) propyl] -4- (2-mercapto-2-methyl-4-aza-pentyl) -4- (2- mercapto-2-methyl-propylamino) piperidine (I) are described in Example 2.

Example 2

Synthesis of 1 - [3- (4-fluorobenzoyl) propyl] -4- (2-mercapto-2-methyl-4-aza-pentyl) -4- (2-mercapto-2-methyl-propylamino) piperidine ( I).

1 - [2'-Propyl-2 '- (4 "-fluorophenyl) -1', 3'-dioxolane] -4-piperidone (E)

To a mixture of 1 5.93 g (65.10 mmol) 2- (3-chloropropyl) -2- (4-fluorophenyl) -1, 3-dioxolane, 17.99 g (130.2 mmol) K ₂ CO ₃ , KI (2g) and 2.30 g (21 .70 mmol) of triethylamine in 100 ml of acetonitrile, 10.0 g (65.10 mmol) of piperidone hydrate hydrochloride were added in portions and the mixture was stirred under reflux for 30 n. After cooling to RT, 50 ml of water were added, the product was extracted with CH ₂ Cl ₂ , the organic phase was dried over Na ₂ SO ₄ and evaporated in vacuo. Chromatographic purification of the residue on silica gel

(EtOAc / acetone, 8: 2) provided 1 6.2 g (90%) of a liquid which solidified when left to stand in the refrigerator.

IR (KBr): [cm ^-1 ]: 3090-3010, 1 610-1460 (Ph), 2950-2880 (Aliph. CH ₂ ), 1 190-1040 (CO of the ketal), 1689 (C = O sat. ).

¹ H-NMR (CDCl ₃ ): δ = 7.4 - 6.9 (m, 4H, aromatic H), 4.1 - 3.7 (m, 4H. OCH ₂ ), 2.75 -2.3 (m, 8H, CH ₂ ), 1.95 - 1.5 (m, 4H, CH _2).

1- [2'-Propyl-2 '- (4 "-fluorophenyl) -1', 3'-dioxalane] -4-cyano-4-aminopiperidine (F)

28.40 g (0.092 mol) of was added to a solution of 6.54 g (0.1 mol) KCN, 5.40 g (0.1 mol) NH ₄ Cl and 4 ml concentrated NH ₄ OH in 20 ml water

Compound E dissolved in 10 ml EtOH, added and stirred at RT for 48 h. The crude product was extracted with methylene chloride. The organic extracts with Washed water, dried over Na ₂ SO ₄ , filtered and evaporated to dryness in vacuo. After chromatographic purification of the residue on silica gel

(CH ₂ Cl ₂ / MeOH 9: 1) 24.0 g (71%) of compound F were isolated.

IR [cm ^-1 ]: 3300 (NH ₂ ), 3090-3030, 1600 (Ph), 2950-2800 (CH ₂ ), 2256 (CN),

1 190-1030 (C-O).

1H-NMR (CDCl ₃ , ppm): 7.83 (m, 2H, ArH), 7.0 (m, 2H, ArH), 4.0 (m, 2H, OCH ₂ ),

3.79 (m, 2H, OCH ₂ ), 2.75-2.50 (m, 4H, CH ₂ ), 2.35 (m, 4H, CH ₂ ), 2.05-1.60 (m,

6H, CH ₂ ), 1.95 (s, 2H, NH ₂ ).

1 - [2'-Propyl-2 '- (4 "-fluorophenyl) -1', 3'-dioxolane] -4-aminomethyl-4-aminopiperidine (G)

To a well-cooled suspension of 0.57 g (1 5 mmol) LiAlH ₄ in 5 ml anhydrous THF, 5.0 g (1 5 mmol) compound F was dissolved in 5 ml THF, slowly added under N ₂ . After 12 h at RT, the mixture was stirred at 70 ° C for 3 h, the excess hydride was destroyed with 20 ml of water-containing THF ether, Al (OH) _{3 was} filtered off, the organic phase was separated, dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was taken up in MeOH and HCl gas was introduced in the cold. The hydrochloride of G was filtered off and dried in vacuo.

IR [cm ^-1 ]: 3180 ( ⁺ NH ₃ ), 3100, 1 590 (Ph), 2940-2800 (CH ₂ ), 1 190-1030 (CO). ¹ H-NMR (free amine, CDCl ₃ , ppm)): 8.00 (m, 2H, ArH), 7.10 (m, 2H, ArH), 4.20 (m, 2H, OCH ₂ ), 3.79 (m, 2H, OCH ₂ ), 3.70 (m, 2H, CH ₂ ), 3.10 (br, 2H, NH ₂ ), 2.75-2.50 (m, 4H, CH ₂ ), 2.35 (m, 4H, CH ₂ ), 2.05-1 .60 (m, 6H, CH ₂ ), 1.95 (s, 2H, NH ₂ ). 3- [2'-Propyl-2 '- (4 "-fluorophenyl) -1', 3'-dioxolane] -3,3,6,6 -tetramethyl-4,5-dithia-1, 8, 13-triazaspiro [9, 10] pentadecane (H).

To a solution of 1.10 g (5.0 mmol) of 2,2'-dithio-bis (2-methylpropanal) in 20 ml of absolute ethanol was added 1.68 g (5.0 mmol) of compound G and stirred at 50 ° C for 60 min. The solvent was removed in vacuo, the residue was dissolved in 30 ml of absolute MeOH and NaBH ₃ CN (5.5 mmol) was added in portions at 0 ° C., the mixture was stirred for 60 min at RT and for 1 day at 40 ° C. 1 5 ml of water were added and the crude product was extracted with dichloromethane. The combined organic phases were dried over Na ₂ SO ₄ , evaporated in vacuo and the residue was purified by chromatography on silica gel (CH ₂ Cl ₂ / MeOH 9: 1). 1.80 g (70%) of compound H was isolated.

IR [cm ^-1 ]: 3230 (NH), 3050, 1590 (Ph), 2900-2830 (CH ₃ , CH ₂ ), 1020 (CO).

1 H-NMR (CDCl ₃ , ppm]: = 7.80 (m, 2H, ArH), 7.10 (m, 2H, ArH), 4.30-3.80 (m, 4H, OCH ₂ ), 3.60-3.20. (M, 4H , CH ₂ ), 3.0 (m, 4H, CH ₂ ), 2.65 (m, 2H, CH ₂ ), 2.48 (m, 6H, CH ₂ ), 2.0-1 .70 (m, 8H, NH, CH ₂ ) , 1 .40-1 .10 (m, 12H, CH _3).

1 - [3- (4-Fluorobenzoyl) propyl] -4- (2-mercapto-2-methyl-4-aza-pentyl) -4- (2-mercapto-2-methyl-propylamino) piperidine (I) .

1.0 g (1.95 mmol) of compound H was dissolved in 5 ml of THF and added to a 0.1 N solution of LiAIH ₄ in THF under N ₂ at 0 ° C. After stirring under reflux for 1 h, the excess hydride was destroyed by carefully adding 5 ml of 0.2 N HCl at 0 ° C. and the pH of the mixture was adjusted to 10 using 0.1 N aqueous NaOH solution. The aqueous suspension was shaken out with (Et) ₂ O, the combined organic phases washed with water, dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. The residue was dissolved in 5 ml 0.1 N

methanolic HCl and boiled at 60 ° C for 1 h. 0.74 g (70%) of the hydrochloride of compound I was isolated after introducing HCl at 0 ° C IR [hydrochloride, cm ^-1 ]: 3150 ( ⁺ NH), 3080-3010, 1590 (aryl), 2900-2830 (CH ₃ , CH ₂ ), 2550 (SH).

¹ H-NMR (CDCI ₃ , ppm) (free base): 8.0 (m, 2H, ArH), 7.10 (m, 2H, ArH), 3.90 -3.10 (m, 4H, CH ₂ ), 2.90 - 2.65 (m, 6H, CH ₂ ), 2.60 (m, 6H, NCH ₂ ), 2.45 - 2.10 (m, 4H, CH ₂ ), 1.90 (s, 4H, NH, SH), 1.30 - 1.1 (m, 12H, CH ₃ ).

The synthesis of the metal complexes according to the general formula II is determined by the properties of the nuclide. While technetium-99m and rhenium-186 require the reduction of the generally available pertechnetate- ^99m Tc and perrhenate- ¹⁸⁶ Re, respectively, which is carried out with tin (II), metals such as indium, gallium, copper and gadolinium can be used directly with the complexing agent be implemented, since they already exist in oxidation states that allow complexation.

The synthesis of the ^99m Tc complex of compound D according to Scheme 3 is described in Example 3.

Scheme 3

Example 3

Representation of a ^99m Tc complex from compound D after addition of

Pertechnetate- ^99m Tc.

1-2 mg of the compound D prepared according to Example 1 were dissolved in 100 μl of methanol and the pH of the solution was increased to 13-14 by adding 100 μl of 1 N aqueous NaOH solution. After adding 250 μl - 500 μl (500-1000 MBq) ^99m Tc pertechnetate and 30 μl SnCl ₂ solution (10 mg SnCl ₂ ×

2 H ₂ O in 1 ml 0.1 N HCl) was allowed to react at RT for 10 min. The technetium-99m complex was obtained with a radiochemical purity of> 90%. Examination with TLC demonstrated the stability of the complex over 6 hours. The determination of the octanol-water distribution coefficient confirmed the formation of a lipophilic compound.

Electrophretic investigations (paper, 0.1 N phosphate buffer pH = 7.8 ° C, 400 V, 60 min) showed that it is a neutral complex.

TLC (ITLC-SG / MEK)

R _f complex = 0.71, ⁹⁹ Tc pertechnetate = 0.90 - 1,

R _f colloidals ⁹⁹ Tc = 0.

TLC (ITLC-SG / 0.9% sodium chloride solution)

R _f complex = 0 - 0.3, ⁹⁹ Tc pertechnetate = 0.9,

R _f colloidals ⁹⁹ Tc = 0.

Distribution of the complex between 1 ml of water and 1 ml of n-octanol:

logP = 1 .28.

Claims

claims

1. Compounds of the general formula I,

in which

RH, - (CHR ₇ ) _a -CH ₂ R ₇ , - (CH ₂ ) _a -C ₆ H ₄ -R ₇ , - (CH ₂ ) _a -C (C ₆ H ₄ -R ₇ ) ₃ , - ( CH ₂ ) _b - (CO) -C ₆ H ₄ R ₇ , - (CHR ₇ ) _a - (CO) -R ₇ , - (CH ₂ ) _b -CH (OH) -C ₆ H ₄ R ₇ , - (CH ₂ ) _b - C (OH) (C ₆ H ₄ -R ₇ ) ₂ , - (CH ₂ ) _b -C (OCH ₂ ) ₂ -C ₆ H ₄ R ₇ , - (CH ₂ ) _a -CH (C ₆ H ₄ -R ₇ ) ₂ , - (CH ₂ ) _b -C (OCH ₂ ) ₃ -C ₆ H ₄ R ₇ .

W, X, Y and Z independently of one another denote N or S,

R ₁ and R ₂ together each represent double-bonded O or S and / or

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R _{7 are the} same or different and H, - (CH ₂ ) _a -CH ₃ , -COOR ', -CONR'R ", OR', SO ₃ R ', -OCOR', -SO ₂ NR'R", - CONHCH ₂ COOH, -SR ' , -NR'R ", -COR ', F, Cl, Br, or I, where

R 'and R "are the same or different and

-COCH ₂ COOH or another suitable sulfur protecting group

R _{7 is} also a 5- or 6-membered heterocycle with 1 to 3

Heteroatoms from the series N, S or O mean, m, n and 0 each independently of one another 0, 1 or 2 and a and b each independently of one another an integer from 0 to

20, preferably from 0 to 10

mean.

2. Compounds of formula I according to claim 1, in which

C ₆ H ₄ R ₇ ,

Y and Z S, preferably together form a disulfide bridge, X and W is N,

R ₁ and R ₂ together form a double bonded oxygen

means and / or

-H, - (CH ₂ ) _a CH ₃ , -COOR ', -CONR'R ", -NR'R" or -OR', where R 'and R "are identical or different and H, - (CH ₂ ) _b CH ₃ ,

Is phenyl or p-hydroxyphenyl,

V denotes -H, -COCH ₃ , -COC ₆ H ₅ or -CH ₂ -C ₆ H ₅ , m, n, o and p are identical and 0, 1 or 2 and

a and b are identical and represent an integer from 0 to 5.

3. Compounds of formula I according to claims 1 or 2, in which m, n and o are identical and 0 or 1, preferably 0, R ₁ and R _{2 are} each hydrogen or R ₁ and R ₂ together are a double bonded O. if they form a carbonylamido structure with the neighboring X or W.

is trained

R ₅ and R ₆ independently of one another are hydrogen or - (CH ₂ ) _a -CH ₃ , where a is an integer from 0 to 5.

4. Complexes correspond to the following general formula II:

in which

R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , V, W, X, Y, Z, m, n and o those for the

Compounds of general formula I according to claims 1 to 3 have meanings and

M ^99m Tc, ⁶⁸ Ga, ^{1 1 1} In, ^{1 13} In, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁶⁷ Cu, ⁶⁴ Cu, ⁶² Cu,

¹⁵³ Gd or a stable gadolinium isotope,

U and T together or independently of one another double-bonded O or S, triple-bonded N, -PKL or H ₂ O, CH ₃ CH ₂ OH,

CH ₃ OH, Cl, Br or I means, wherein

K and L are -OR ', -H, - (CH ₂ ) _b CH ₃ , - (CH ₂ ) _a -O- (CH ₂ ) _b -CH ₃ , where R' are those mentioned for compounds of the general formula I.

Has meanings and a and b are independently 0 to 10,

p and q are independently 0 or 1.

5. Compounds according to claim 4, in which U and T are either O, N or S, where p and q each represent 1, p 1 and q 0, or p and q 0.

6. Compounds according to claims 4 or 5, wherein M is 99m-Tc.

7. A process for the preparation of a compound of general formula II according to claims 1 to 3, characterized in that reacting a compound of general formula I with a metal compound of a metal M.

8. Use of a compound of general formula II according to

Claims 1 to 3 as a non-invasive functional diagnostic in nuclear medicine.

9. Diagnostic agent containing a compound of general formula II.