JP2001516730A - Methods for therapeutically treating proliferative disorders - Google Patents

Abstract

(57) The present invention relates to a method for therapeutically treating a proliferative disease, which comprises first inserting a catheter to be used at a site of injury, and administering a radioactive substance locally through the catheter. Subsequently, the catheter is removed again to allow radioactive material to remain at the site of the injury. The invention further relates to the use of bisamine oxime derivatives, derivatives of N ₂ S ₂ complexes and radiolabeled colloid solutions for the manufacture of a medicament, which are administered topically in the treatment of a proliferative disease .

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to the treatment of proliferative disorders, and in particular to the area of treating vascular diseases such as, for example, atherosclerosis.

It is well known that ionizing radiation inhibits cell growth. With this method,
Many neoplastic and non-neoplastic diseases have already been treated [Fletcher, "Textbook of Radiotherapy", Philadelphia, P. et al.
A: Lea and Febiger, 1980, Hall, "Radiobio for Radiologists
philosophy for the Radiologist), Philadelphia, PA: Lippincott, 1988).

[0003] It has also been attempted to treat atherosclerotic diseases using this method. Atherosclerosis is an inflammatory fibroproliferative disorder that accounts for 50% of all deaths in the United States, Europe and Japan (Ross 1993, "
Nature "362: 801-809). When the disease appears peripherally, limb maintenance is threatened, coronary manifestations are at risk of myocardial infarction leading to death, and the upper aorta
Threatened by a stroke attack.

[0004] Atherosclerosis is currently treated in various ways. In addition to conventional procedures (eg, reducing cholesterol levels in blood) and bypass surgery, alternatives include mechanical dilation of blood vessels (angioplasty) and atheroma of stenotic areas in peripheral and coronary arteries. A method of removing tissue from an internal blood vessel (atherectomy) has also been established in daily medical care.

[0005] However, as will be described in more detail below, the above-mentioned method has a number of disadvantages. Methods of mechanically revascularizing blood vessels are compromised by acute vaso-occlusion and acute thrombosis following vascular rupture and dissection (Sigwart et al. 1987, "N.
Engl.J.Med. "316: 701-706). Long-term success has been compromised by the re-emergence of stenosis (restenosis). According to the CAVEAT study, the proportion of 1012 patients who developed restenosis 6 months after the intervention was 50% with coronary atherectomy,
In coronary angioplasty, it was 57% (Topol et al. 1993, "N. Engl. J.
Med. "329: 221-227). In this study, an additional 7% of atherectomy patients and 3% of angioplasty patients suddenly developed vascular occlusion. Nicolini and Pepine (1992,
According to the report by Endovascular Surgery 72: 919-940), the rate of restenosis occurring after angioplasty is between 35 and 40% and the rate of acute occlusion is 4%.

Various techniques have been developed to address such complications. One of them is to implant a metallic endoprosthesis (stent) (Sigwart et al. 1987,
N. Engl. J. Med. 316: 701-706; Strecker et al., 1990, Radiology 175.
: 97-102). For example, implanting a stent into a large-diameter artery when the pelvic axis is occluded has already gained the first rank as a method applied to treatment. In contrast, using a stent in the femoral artery resulted in a 49% initial opening rate and a 43% reocclusion rate, with disillusioning results (Sapoval et al., 1992, Radiology 184: 8).
33-839). Similarly unsatisfactory results have been obtained with stents previously used for coronary arteries (Kavas et al. 1992, "J. Am. Coll. Cardiol." 20: 467-474).

[0007] To date, restenosis has not been arrested using all existing pharmacological and mechanical interventions (Muller et al. 1992, "J. Am. Coll. Cardiol.
19: 418-432, Popma et al. 1991, Circulation 84: 14226-1436). One possible cause of restenosis, which often occurs after mechanical surgery, is that the surgery induces smooth muscle growth and migration in the vascular wall. This results in neointimal hyperplasia and restenosis is observed in the treated vascular segments (Cascells 1992, Ci
rculation ”86: 723-729, Hanke et al. 1990,“ Circ.Res. ”67, 651-659, R
oss 1993, Nature 362: 801-809).

[0008] There are other methods of using ionizing radiation to treat atherosclerotic disease. However, when ionizing radiation incident from the external system is used to treat restenosis, its disadvantages are accompanied by the fact that the radiation dose reaches not only the target site but also its surroundings (
Even healthy tissue is similarly exposed to radiation, leading to undesirable consequences.
For this purpose, various studies have been conducted, but the results have been limited (Gellmann
et al. 1991, “Circulation” 84 Suppl. II: 46A-59A, Schwartz et al. 1992,
"J. Am. Coll. Cardiol." 19: 1106-1113).

[0009] Obstacles that occur when using an external source can be eliminated, for example, when gamma rays reach the vascular site of restenosis directly through a catheter, for example. A high dose of 20 Gy is given to the restenosis group by the mode using iridium-192. Following this intervention, some studies have reported that restenosis is almost completely arrested (Wiedermann et al. 1994, "Am. J. Physiol.
267: H125-H132, B ⁶ ttcher et al. 1994, Int.J. Radiation Oncology Biol.
.Phys. "29: 183-186, Wiedermann et al. 1994," J.Am.Coll.Cardiol. "23: 1
491-1498, Liermann et al. 1994, "Cardiovasc.Intervent.Radiol." 17: 12-
16) However, a disadvantage of these methods is that the used dose of 20 Gy is very high. Due to the irregular distribution of the lesions on the vessel wall, it is not possible to deliver a defined dose uniformly using this technique. In addition, the low dose of the iridium source limits the ability to treat large diameter vessels with sufficient dose.

[0010] Another possibility to prevent restenosis is a P-32 doped stent (Fisc
hell et al. "Stents III, development, compatibility and future (StentsIII, Entwicklung
, Indikationen und Zukunft), Konstanz: Kollath und Lieremann, 1995)
There is a way to implant. In this study, P / cm
A radioactivity of 0.2 kBq by -32 (corresponding to a dose of 0.25 Gy) was used, which was sufficient to maximally inhibit smooth vascular myocytes in vitro. As a result, it was shown that not only the γ-emitter but also the β-emitter can inhibit the proliferation of smooth muscle cells. The advantage of this method is that the doses used are clearly lower than any previously described intervention. Due to the low dose, endothelial cells covering the vascular bed are not damaged (Fischell et al. "Stents III, development, compatibility and future (Stents III, Entwicklung, Indikationen und Zukunft)", Konstanz: Koll
ath und Lieremann, 1995). And the type of intervention is only possible once, ie when positioning the stent. Moreover, this method is limited to interventions using stents only. In addition, such as atherectomy and angioplasty,
Restenosis that develops during frequently used interventions cannot be treated using this method. Due to the short reach of β-radiation, it has not been possible to give a uniform energy dose to the entire lesion.

[0011] In addition to radiation therapy, a range of other therapeutic strategies have also been used to inhibit neoendothelial hyperplasia (restenosis). These include classic drugs that inhibit restenosis, including antithrombotic agents, platelet aggregation inhibitors, calcium antagonists, anti-inflammatory and antiproliferative agents, and also gene therapy agents. In this case, for example, inhibition of growth promotion by an antisense oligonucleotide, enhancement of an inhibitor by an expression vector plasmid, and virus-mediated gene integration are possible. Aptamer oligonucleotides can also be used to block processes mediated by various receptors and playing a key role in restenosis.

Over the years, with considerable energy and attention, the study of drug substances administered for long-term treatment under strictly controlled conditions has been based on the incidence of restenosis. Is theoretically desired to be reduced (Herrman
n et al., 1993, "Drugs" 46 : 18-52). More than 50 comparative studies using different substance groups did not provide any clear evidence that the test substance significantly reduced the incidence of restenosis. This result is also true for topical administration, in which the substance is in each case injected through a special balloon catheter to the desired site. Moreover, it has been shown that the substances conventionally used are quickly washed away from the blood vessel wall and are insufficient to exert a therapeutic effect. In addition, solution injection via pressure results in concomitant changes in the vessel wall, thereby promoting even restenosis.

[0013] Accordingly, an object of the present invention was to develop a method for treating a proliferative disease, overcoming the drawbacks of conventionally known treatments. This problem is solved by the following invention. Methods have been developed to treat proliferative disorders, which are characterized by first inserting the catheter to be used at the site of the injury, and administering the radioactive material locally through the catheter, and subsequently removing the catheter again. Therefore, radioactive material is left at the site of the injury.

By administering and allowing radioactive material to remain on the target vessel wall by application of a catheter, the radionuclide is maintained at a concentration sufficient to inhibit cell growth and consequent restenosis over time. Dripping. The method according to the invention has several essential advantages over known treatment methods. Compared to a large number of test compounds from different classes, the local administration of a particular substance using a particular catheter results in a surprisingly high dose of radioactivity at the site of a pathologically altered target. Granted. In this process, the load on the system is reduced and a high radiation dose that works effectively is obtained. This radioactive material stays at the site of administration for a long period of time and emits a high dose from which it works. These substances are distributed particularly uniformly in the pathological area. Unbound radioactive material is immediately removed.

When a specific radioactive substance, which will be described in detail below, reaches the blood vessel wall changed by atherosclerosis, not only the intimal cells facing the cavity but also the cells of the medium and the outer membrane,
Inhibits its growth. The fraction of the administered dose that crosses the cell membrane emits a high radiation dose and works effectively near the cell nucleus. In order for the proliferating cells to be sensitive to ionizing radiation, the method according to the invention comprises:
It is suitable not only for treating atherosclerotic diseases, but also for treating other proliferative diseases such as, for example, tumor diseases.

Suitable radioactive substances exhibit a sufficiently high lipophilicity and remain attached to the hemolytic plaque. An example is a radiolabeled metal complex, such as, for example,
A metal complex comprising a bisamine oxime derivative represented by the general formula I,

[0017]

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Wherein n = 0 to 3 and the residues R ^{1 to} R ⁸ are the same or different and are each hydrogen and / or unbranched, branched, cyclic or polycyclic C ₁ -C ₁₀₀ - alkyl residue, - alkenyl residue, - alkynyl residues, - aryl residue, - alkyl aryl residues and / or arylalkyl residue, this residue can, if necessary,
A hydroxy, oxo, carboxy, aminocarbonyl group containing fluorine, chlorine, bromine and / or iodine and / or up to 30 carbon atoms,
By one or more heteroatoms substituted by an alkoxycarbonyl group, an amino group, an aldehyde group or an alkoxy group and / or, if necessary, from the series N, P, As, O, S, Se. Truncated and / or substituted, wherein the residues R ² and R ³ , R ⁴ and R ⁵ and R ⁶ and R ⁷ are optionally
Together they may represent an oxygen atom.

These compounds form a metal complex with the radionuclide, which metal complex is used for topical administration in the treatment of a proliferative disease. Metal complexes of N ₂ S ₂ derivatives of the general formulas II and III are likewise suitable:

[0020]

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Where R⁹~ R³²Are equal or different, each being a hydrogen atom and / or unbranched
, Branched, cyclic or polycyclic C₁-C₁₀₀-Alkyl residue, -alkenyl residue
, -Alkynyl residue, -aryl residue, -alkylaryl residue and / or
Represents a fluoroalkyl or chlorine atom, if necessary.
Hydrogen containing bromine, bromine and / or iodine and / or up to 30 carbon atoms
Roxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl
Substituted by an alkyl group, an amino group, an aldehyde group or an alkoxy group, and / or
, If necessary, one or more of the series N, P, As, O, S, Se
Cleaved and / or substituted by the above heteroatoms, and wherein the residue R¹¹And R ¹² , R¹³And R¹⁴, R^FifteenAnd R¹⁶And R¹⁷And R¹⁸If necessary,
May together represent an oxygen atom, and n, m and p are each independently
Means 1 or 2.

Other suitable compounds include those suitable for topical treatment by forming a complex with a suitable radioisotope, including tetrofosmin derivatives, sestamibi derivatives and flifhosmin derivatives. ^99m Tc-tetrofosmin is
Available under the trade name Myoview ™ from Amersham, ^99m T
c-Sestamibi is available under the trade name Cardiolite® from DuPont.
And ^99m Tc-flifosmin can be purchased from Mallinckrodt Medical under the trade name TechneScan Q-12.

All of these compounds form a metal complex with the radionuclide and are used for topical administration in the treatment of proliferative disorders. Radionuclides are introduced to form metal complexes, these are alpha emitters,
Beta emitters and / or gamma emitters, positron emitters, Auger electron emitters and fluorescent emitters, of which the beta emitters and the combined beta / γ emitters are excellent for therapeutic purposes.

[0024] Corresponding radionuclides are known to the expert. For example, atomic numbers 27 and 29
~ 32, 37-39, 42-51, 62, 64, 70, 75, 77, 82 or 8
And a radionuclide of the element having the number 3. Preferred nuclides are^99mTc,¹⁸⁶Re,¹⁸⁸Re,⁶⁷Cu,⁹⁰Y, and ¹⁰⁷ Ag, a particularly preferred nuclide, is¹⁸⁶Re,¹⁸⁸Re and⁶⁷Cu
.

The preparation of bisamine oxime derivatives is described in US Pat. Nos. 5,506,345 and 5,387,692, and the preparation of N ₂ S ₂ derivatives is described in US Pat. No. 5,279,811. . The preparation of tetrofosmin derivatives is described in European Patent Application EP 303 374, and the preparation of furifosmin derivatives is described in US Pat. No. 5,112,595. International patent application WO 89/024 for sestamibi derivatives and their production
No. 33.

Further suitable metal complexes have a ligand, which can be formed from ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA) or a macrocyclic compound such as, for example, tetraazacyclododecane. Be guided. The preparation of these compounds is known to the expert and is further described in the following examples. Other suitable ligands are, for example, porphyrin derivatives, which are described, for example, in DE 42 32 925 (A1) and DE 43 05
No. 523 (A1). From these ligands, a radionuclide can be used to produce a metal complex suitable for the method of the present invention.

Similarly, radioactive thallium compounds with the isotopes ²⁰¹ Tl, ²⁰⁷ Tl, ²⁰⁹ Tl and ²¹⁰ Tl are suitable, in particular ²⁰¹ TlCl. Radioactively labeled colloidal solutions are also very suitable for the treatment of proliferative disorders and especially for topical administration. Suitable colloidal solutions are the tin-colloids described in the examples; particularly suitable tin colloids can be prepared using kits from Amersham ("Amerscan Zinnkolloid ( ^99m Tc) -liver scintigraphy"). Signage kit for
). Other suitable colloids include, for example, radioactive gold sols ( ^198Au colloids) and radioactively labeled sulfur colloids and other physiologically compatible radioactive colloid solutions.

Suitable radionuclides for radiolabeling colloidal solutions are known to the expert. As examples, the elements Ag, As, At, Au, Ba, Bi, Br, C
, Co, Cr, Cu, F, Fe, Ga, Gd, Hg, Ho, I, In, Ir, L
u, Mn, N, O, P, Pb, Pd, Pm, Re, Rh, Ru, Sb, Sc, S
e, Sm, Sn, Tb, Tc or Y radionuclide.

[0029] Especially preferred species are ^{99m Tc, 186 Re, 188 Re} , 67 Cu, 90 Y, 15 3 Sm, 160 Tb, 162 Tb, 198 Au and ¹⁰⁷ Ag. The colloid solution is generally produced in an aqueous solution or an alcoholic solution in which a radioactive salt is present by a redox reaction or by changing the pH value. The colloid can be formed in the presence of a stabilizer, or a surfactant or other stable type of amphiphile can be added later. Other methods for preparing suitable colloidal solutions include electrochemical techniques, such as those described by MT Reetz et al. In "Angew. Chem." 1995, Vol. 107, pages 2461 et seq. The production of tin colloid is described in the following examples and in the instruction manual of the labeling kit manufactured by Amersham. The production of colloidal gold for diagnostic purposes is described in German Patent DE 24 20 531 (C3).

The size of the particles produced is in the range between 5 and 1000 nm, and in the case of tin colloids in the range 300 to 600 nm. As a catheter suitable for local administration of the substance according to the invention, the catheter illustrated in FIG. 3 can be used. Particularly suitable are multi-lumen balloon catheters (eg, Dispatch ™, SciMed, etc.) and microporous balloon catheters.

The following examples describe the methods used in animal experiments. The preparation of a number of other compounds suitable for this treatment is described. The methods in Examples 1-5 use ^99m Tc-labeled HMPAO, where the ligand HMPAO has the following structure:

[0032]

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(Additionally, “Radiation Drugs, Chemistry and Pharmacology” edited by Adrian D. Nunn (Radiophar
maceuticals, Chemistry and Phar-macology ”, 1992, p. 53). Example 1 Topical administration of ^99m Tc-HMPAO White rabbits from New Zealand, a test animal (internal animal registration number 1708,
The following preparations were made four weeks before the original dosing experiment for males, weighing 3.7 kg).

Under anesthesia (Rompun / Ketavet 1: 2, 1 ml / kg body weight, intramuscular administration), the endothelium of the right carotid artery was injured using a 2F Fogarty balloon catheter (balloon detachment). . Subsequently, the animals were fed a special diet containing 0.2% cholesterol. This pretreatment results in atherosclerotic lesions where the test animal has undergone balloon denudation.

Topical administration of technetium-99m-labeled HMPAO was performed using a coronary perfusion / infusion catheter (Dispatch 3.0, Extra Smooth Coating, manufacturer: Boston Scientific Co.)
rporation, Rating) and immediately to the lesion site in the carotid artery of the test animals anesthetized (see above for mode of anesthesia). 0.48 mCi (= 17.76 MBq)
Was administered in a volume of 0.85 ml.

The test animals are placed under a gamma camera (Elscint SP4 HR) throughout the experiment to determine the distribution of radioactivity in the body. Radioactivity at the site of injury is shown as a percentage of total radioactivity (measured at this point in the animal). The following results were obtained for this test animal. 5 minutes after administration 55.38% of the dose at the site of injury 4 minutes after administration 46.78% of the dose at the site of injury 24 minutes after administration 21.45% of the dose at the site of injury Example 2 ^99m Tc-HMPAO, a local animal test animal from New Zealand White rabbit (internal animal registration number 1856,
Male, body weight 3.3 kg), the following preparations were made 4 weeks before the original administration experiment.

Under anesthesia (Rompun / Ketavet 1: 2, 1 ml / kg body weight, intramuscular administration), the endothelium of the right carotid artery was injured using a 2F Fogarty balloon catheter (balloon exfoliation). . Subsequently, the animals were fed a special diet containing 0.2% cholesterol. This pretreatment results in atherosclerotic lesions where the test animal has undergone balloon denudation.

[0038] Topical administration of technetium-99m-labeled HMPAO was performed using a coronary perfusion / infusion catheter (Dispatch 3.0, extra smooth application, manufacturer: Boston Scientific Co.)
rporation, Rating) and immediately to the lesion site in the carotid artery of the test animals anesthetized (see above for mode of anesthesia). A dose emitting 1.91 mCi (= 70.67 MBq) was administered in a volume of 1.0 ml (later washed with 0.3 ml of saline).

The test animals are placed under a gamma camera (Elscint SP4 HR) throughout the experiment to determine the distribution of radioactivity in the body. Radioactivity at the site of injury is shown as a percentage of total radioactivity (measured at this point in the animal). The following results were obtained for this test animal. 5 minutes after administration 40.74% of the dose at the site of injury 4 minutes after administration 35.13% of the dose at the site of injury 24 minutes after administration 23.69% of the dose at the site of injury Example 3 A test animal for local administration of ^99m Tc-HMPAO was from New Zealand. This is a white rabbit (internal animal registration number 1584, male, weighing 3.4 kg).

Under anesthesia (Lombom / Ketavet 1: 2, 1 ml / kg body weight, intramuscular administration), the endothelium of the infrarenal aorta was injured using a balloon catheter (balloon exfoliation). Subsequently, HMPAO labeled with 99m of technetium was applied to the animals for 5 minutes using a microporous balloon catheter (4 mm Match-35 PTA, Schneider,
FRG). A dose emitting 0.64 mCi (= 23.68 MBq) was administered in a volume of 1 ml.

The test animals are placed under a gamma camera (Elscint SP4 HR) throughout the experiment to determine the distribution of radioactivity in the body. Radioactivity at the site of injury is shown as a percentage of total radioactivity (measured at this point in the animal). The following results were obtained for this test animal. 5 minutes after administration 38.45% of the dose at the site of injury 4 minutes after administration 35.64% of the dose at the site of injury 24 minutes after administration 16.63% of the dose at the site of injury Example 4 The test animal for local administration of ^99m Tc-HMPAO was from New Zealand. Were white rabbits (internal animal registration number 1587, male, weight 3.5 kg).

Under anesthesia (Lombom / Ketavet 1: 2, 1 ml / kg body weight, intramuscular administration), the endothelium of the infrarenal aorta was injured using a balloon catheter (balloon detachment). Subsequently, HMPAO labeled with 99m of technetium was applied to the animals for 5 minutes using a microporous balloon catheter (4 mm Match-35 PTA, Schneider,
FRG). A dose emitting 1.18 mCi (= 46.66 MBq) was administered in a volume of 1 ml.

The test animals are placed under a gamma camera (Elscint SP4 HR) throughout the experiment to determine the distribution of radioactivity in the body. Radioactivity at the site of injury is shown as a percentage of total radioactivity (measured at this point in the animal). The following results were obtained for this test animal. 5 minutes after administration 37.06% of the dose at the site of injury 4 minutes after administration 32.03% of the dose at the site of injury 24 minutes after administration 20.01% of the dose at the site of injury Example 5 The test animals for local administration of ^99m Tc-HMPAO were from New Zealand. Were white rabbits (internal animal registration number 1586, male, weighing 3.3 kg).

Under anesthesia (Lombung / Ketavet 1: 2, 1 ml / kg body weight, intramuscular administration), the endothelium of the infrarenal aorta was injured using a balloon catheter (balloon exfoliation). Subsequently, HMPAO labeled with 99m of technetium was applied to the animals for 5 minutes using a microporous balloon catheter (4 mm Match-35 PTA, Schneider,
FRG). A dose emitting 0.45 mCi (= 16.65 MBq) was administered in a volume of 1 ml.

The test animals are placed under a gamma camera (Elscint SP4 HR) throughout the experiment to determine the distribution of radioactivity in the body. Radioactivity at the site of injury is shown as a percentage of total radioactivity (measured at this point in the animal). The following results were obtained for this test animal. 5 minutes after administration 45.56% of the dose at the site of injury 4 minutes after administration 36.39% of the dose at the site of injury 24 minutes after administration 15.24% of the dose at the site of injury

[0046] Example 6 1- {3- [N-(2-methoxyethyl) - octadecyl sulfamoyl] -2 - hydroxy - propyl} 4,7,10-tetraaza - cyclododecane, said thorium -90- Preparation of complex 1- {3- [N- (2-methoxyethyl) -octadecylsulfamoyl]-
5 mg of 2-hydroxypropyl｝ -4,7,10-tetraaza-cyclododecane (produced according to German Patent DE 4340809.5) are treated with 500 μl of dimethyl sulfoxide.
and 50 μl of 0.1 M sodium acetate buffer (pH = 4.0). 37M
After adding the yttrium-90-trichloride solution of Bq, the reaction mixture is heated to 100 ° C. for 10 minutes. The yttrium-90-complex solution thus prepared can be used without further purification.

[0047] Example 7 a) N, N'- Bisuundeshiru - diethylene - triamine - pentaacetic acid - diamide manufacturing diethylene - triamine - the pentaacetic acid dianhydride 3.57 g (10 mmol), anhydrous dimethylformamide 100 ml of 4.05 g (40 mmol) of triethylamine in
Suspend with. Subsequently, at room temperature, a solution of 3.42 g (20 mmol) of undecylamine in 50 ml of water-free dichloromethane is added dropwise to the reaction mixture. The reaction stock solution was stirred at room temperature for 6 hours, filtered, and
Evaporate and concentrate. The residue is dissolved three times in 100 ml of dimethylformamide and in each case concentrated by evaporation under medium high vacuum. The foamy reaction product is poured into 50 ml of water-free diethyl ether and stirred overnight. Perform filtration and dry under medium-high vacuum. Yield: 6.3 g (90%), white powder Elemental analysis: Calculated: Carbon 61.77 Hydrogen 9.94 Nitrogen 10.01 Oxygen 18.86 Experimental: Carbon 61.52 Hydrogen 9.63 Nitrogen 9.91 Oxygen

[0048] b) N, N'Bisuundeshiru - diethylenetriamine - pentaacetic acid - diamide, Lee Ttoriumu -90- complex manufacturing N, N'Bisuundeshiru - diethylenetriamine - pentaacetic acid diamide (Example 7a) and 5 mg, dimethyl sulfoxide Dissolve in 500 μl and 50 μl of 0.1 M sodium acetate buffer (pH = 4.0). After adding 37 MBq of yttrium-90-trichloride solution, the reaction mixture is left at room temperature for 10 minutes. The Y-90-complex solution thus prepared can be used without further purification.

[0049] Example 8 a) N- benzyloxycarbonyl - glycyl -N'- undecyl - Gurishin'a bromide To a solution of N- benzyloxycarbonyl - glycyl - glycine -N- hydroxysuccinimide ester 3.63 g (10 mmol) and undecyl amine 1.71 g (10 mmol)
Is dissolved in 100 ml of water-free dichloromethane. The reaction mixture is heated at room temperature for 6 hours.
Stir for hours. It is subsequently diluted with 100 ml of dichloromethane and the organic phase is washed twice with 50 ml of a saturated solution of sodium hydrogen carbonate and once with 50 ml of water. It is dried over magnesium sulfate and the solvent is evaporated in vacuo. The crude product is purified by chromatography on silica gel (eluent: dichloromethane / methanol 95: 5). Yield: 3.8 g (90.6%), white powder Elemental analysis: Calculated: 65.84 hydrogen 8.89 nitrogen 10.01 oxygen 15.25 Experimental: 65.71 hydrogen 9.02 nitrogen 10.10 oxygen

B) Preparation of glycyl-N′-undecyl-glycinamide 3 g (7.15 mmol) of N-benzyloxycarbonyl-glycyl-N′-undecyl-glycinamide (Example 8a) were added to 100 ml of water-free ethanol. Dissolve in After adding 300 mg of palladium on carbon (concentration 10%), the mixture is hydrogenated for 2 hours at room temperature (1 atm of hydrogen). Filter and evaporate in vacuo. The obtained amine is used for the next reaction without further purification. Yield: 1.92 g (94.1%), white foam Elemental analysis: Calculated: 63.12 hydrogen 10.95 nitrogen 14.72 oxygen 11.21 experimental: 63.03 hydrogen 11.04 nitrogen 14.57 oxygen

[0051] c) N-(S- acetyl - mercaptoacetyl) - glycyl -N'- undecyl - glycinamide manufacturing glycyl -N'- undecyl - glycinamide (Example 8b) 285.4 mg (1 m
mol) and 231.2 mg (1 mmol) of S-acetyl-mercapto-acetic acid-N-hydroxy-succinimide ester are dissolved in 20 ml of water-free dichloromethane. The reaction mixture is stirred at room temperature for 6 hours. Subsequently, the mixture is diluted with 20 ml of dichloromethane and the organic phase is washed twice with 5 ml of a half-saturated solution of sodium hydrogen carbonate and then with water.
Wash once with 5 ml. It is dried over magnesium sulfate and the solvent is evaporated in vacuo. The crude product is purified by chromatography on silica gel (eluent: dichloromethane / methanol 93: 7). Yield: 362 mg (90.1%), white powder Elemental analysis: Calculated: carbon 56.83 hydrogen 8.79 nitrogen 10.46 oxygen 15.94 sulfur 7.98 Experimental: carbon 56.67 hydrogen 8.93 nitrogen 10.18 oxygen sulfur 7.72

[0052] d) N-(mercaptoacetyl) - glycyl -N'- undecyl - Gurishin'ami de fabrication N-(S- acetyl - mercaptoacetyl) - glycyl -N'- undecyl -
201 mg (0.5 mmol) of glycinamide (Example 8c) was added to ethanol
Dissolve in 15 ml. The solution is saturated with argon and ammonia flows into the solution for 30 minutes. Subsequently, the mixture is concentrated by evaporation, and the residue is taken up in 20 ml of dichloromethane.
The organic phase is shaken once with a 2% aqueous citric acid solution and dried over sodium sulfate. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane / methanol 9: 1). Yield: 153 mg (85.1%), white powder Elemental analysis: Calculated: carbon 56.79 hydrogen 9.25 nitrogen 11.69 oxygen 13.35 sulfur 8.92 Experimental: carbon 56.67 hydrogen 9.43 nitrogen 11.48 oxygen sulfur 8.71

[0053] e) N- (mercaptoacetyl) - glycyl -N'- undecyl - Gurishin'ami de production of Re-186- complex N- (mercaptoacetyl) - glycyl -N'- undecyl - glycinamide (Example 8d) Dissolve 5 mg in 800 μl of ethanol. After adding 5 mg of disodium L-tartrate and 50 μl of 0.1 M sodium hydrogen phosphate buffer (pH = 8.5), 10 μl of a solution of 37 MBq of perrhenate and tin dichloride dihydrate (5 μL) were added.
mg SnCl ₂ × 2 H ₂ O / 1 ml 0.1 M HCl). The reaction mixture is heated to 60 ° C. for 5 minutes. N- (mercaptoacetyl)-thus prepared
The Re-186 complex solution of glycyl-N'-undecyl-glycinamide can be used without further purification.

Example 9 N, N'-bis [3,6,9,9-tetra (hydroxycarboxymethyl) -1 -oxo-3,6,9-triaza-non-1-yl] -mesoporphyrin- Preparation of IX- 13,17-dihydrazide, Y-90-complex N, N'-bis [3,6,9-tri (hydroxycarboxymethyl) -9- (
(Ethoxycarboxymethyl) -1-oxo-3,6,9-triaza-non-1-
Il] -mesoporphyrin-IX-13,17-dihydrazide (German Patent DE
42 32 925 (A1), prepared according to Example 1a) 5 mg in 0.1 M NaOH 5 m
Stir for 3 hours at room temperature under an argon atmosphere in l. Subsequently, after saponification of the bisethyl ester (DC check), the pH is adjusted to 6 with acetic acid and 37 MBq of yttrium-90-trichloride solution are added. This is stirred at room temperature for 15 minutes. HPLC analysis shows that 95% of the radioisotope
Is incorporated.

Example 10 Preparation of 5,10,15,20-tetrakis- [3- (carboxymethoxy) -phenyl ] -porphyrin and yttrium-90-complex 5,10,15,20- tetrakis- [3- ( (Carboxymethoxy) -phenyl] -porphyrin (German Patent DE 43 05 523 (A1), prepared according to Example 13a) 2.0 mg are dissolved in 5 ml of acetic acid to give 1.0 mCi of yttrium-
Add 90-chloride in hydrochloric acid solution. The reaction mixture is placed in an autoclave for 14 hours.
The mixture is treated at 0 ° C. for 1 hour, the solvent is evaporated off under vacuum, and the residue is
To be collected. The pH is adjusted to 7.3 by dropwise addition of aqueous sodium bicarbonate solution and the resulting red solution is filtered through a membrane filter. The filtrate is subjected to HPLC
When checked in,> 95% of the radioactivity used is incorporated into the porphyrin ligand.

Example 11 Preparation of 5,10,15,20-tetrakis- [3- (carboxymethoxy) -phenyl ] -porphyrin, copper-67-complex The preparation of this complex is described in German Patent DE 43 05 523. (A1) Example 14
It is described in. Example 12 Preparation of technetium-99m-tin-colloid 555 MBq of sodium pertechnetate in 2 ml of 0.9% sodium chloride solution was added at room temperature to a tin (II) chloride solution (tin (II) chloride dihydrate 5). mg
/ 0.01 M HCl 1 ml) to 20 μl. After 10 minutes, add 1 ml of PBS buffer to dilute. The resulting solution has a pale milky color.

Example 13 Preparation of rhenium-186-tin-colloid 37 MBq of sodium perrhenate in 2 ml of 0.9% sodium chloride solution was added at room temperature to a tin (II) chloride solution (tin (II) chloride). Hydrate 5 mg / 0.
01 M HCl (1 ml) to 40 μl. After 10 minutes, add 1 ml of PBS buffer to dilute. The resulting solution has a pale milky color. Example 14 The test animal for topical administration of tin-colloid is a white rabbit from New Zealand (internal animal registration number 1852, male, 3.5 kg in weight).

Under anesthesia (Lombung / Ketavet 1: 2, 1 ml / kg body weight, intramuscular administration), the endothelium of the infrarenal aorta was injured using a balloon catheter (balloon exfoliation). The animals were subsequently administered a colloidal tin for 5 minutes using a microporous match catheter (5 mm diameter balloon catheter, manufacturer: Schneider, Düsseldorf), which was obtained from Amersham. company kit ^{( "Amerscan Zinnkolloid (99m Tc)} - labeling kit liver scintigraphy") manufactured by. The dose at which 0.4 mCi (= 14.8 MBq) is emitted should be
The dose was adjusted to 1 ml.

The test animals are placed under a gamma camera (Elscint SP4 HR) throughout the experiment to show the distribution of radioactivity in the body. In the upper part of FIG. 1, the state before administration is shown. The catheter containing the tin colloid is clearly visible. The arrow represents the balloon of the catheter, which is located at the desired administration site. The lower part of the photograph shows the same position when the catheter was removed 1.5 hours after administration. The amount of tin colloid remaining at the site of administration is clearly confirmed. Example 15 The test animal for topical administration of tin-colloid is a white rabbit from New Zealand (internal animal registration number 1839, male, weighing 3.7 kg).

Under anesthesia (Lombung / Ketavet 1: 2, 1 ml / kg body weight, intramuscular administration), the endothelium of the infrarenal aorta was injured using a balloon catheter (balloon exfoliation). The animals were subsequently administered a colloidal tin for 5 minutes using a microporous match catheter (5 mm diameter balloon catheter, manufacturer: Schneider, Düsseldorf), which was obtained from Amersham. company kit ^{( "Amerscan Zinnkolloid (99m Tc)} - labeling kit liver scintigraphy") manufactured by. The dose at which 0.47 mCi (= 17.39 MBq) is emitted is adjusted to a volume of 0.
The dose was adjusted to 1 ml.

Test animals are placed under a gamma camera (Elscint SP4 HR) throughout the experiment to display the distribution of radioactivity in the body. In the upper part of FIG. 2, the state before administration is shown. The catheter containing tin-colloid is clearly visible. The arrow represents the balloon of the catheter, which is located at the desired administration site. The lower part of the photograph shows the same position when the catheter was removed 1.5 hours after administration. The amount of tin colloid remaining at the site of administration is clearly confirmed.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int. Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 35/00 A61K 43/00 (31) Priority claim number 197 42 880.0 (32) Priority date Heisei 9 September 23, 1997 (September 23, 1997) (33) Countries claiming priority Germany (DE) (81) Designated States EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG) , AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, Z, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS , JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Blume, Friedhelm Germany, Day -13505 Berlin, Nusselherstrasse 47 F Term (reference) 4C084 AA12 MA21 MA66 NA13 ZA452 ZB262 4C206 HA01 JA55 JB01 JB03 JB04 JB06 JB07 JB08 JB11 JB20 MA01 MA04 MA41 MA86 NA13 NA14 ZA45 ZB26

Claims (29)

[Claims] 1. Inserting the catheter to be used into the lesion at first, and administering the radioactive substance locally through the catheter, followed by removing the catheter again and leaving the radioactive substance at the lesion. A method for treating and treating a proliferative disease characterized by the above. 2. Inserting the catheter to be used into the lesion site first, and administering the radioactive material locally through the catheter, followed by removing the catheter again, leaving the radioactive material at the lesion site. A method for treating and treating atherosclerotic disease. 3. The method according to claim 1, wherein the radioactive substance is a metal complex. 4. The radioactive substance is a metal complex, whose ligand is represented by the general formula I: Wherein n = 0-3, and the residues R ¹ -R ⁸ are the same or different and each is a hydrogen atom and / or an unbranched, branched, cyclic or polycyclic C ₁ -C ₁₀₀ -alkyl residue, -alkenyl residue,-
Represents an alkynyl residue, an -aryl residue, an -alkylaryl residue and / or an arylalkyl residue, which, if necessary, is a fluorine atom, a chlorine atom,
Substituted by a bromine and / or iodine atom and / or a hydroxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy group containing up to 30 carbon atoms, and / or If necessary, is cleaved and / or substituted by one or more heteroatoms of the series N, P, As, O, S, Se, wherein the residues R ² and R ³ , R ⁴ and R ⁵ , and R ⁶ and R ⁷ may together represent an oxygen atom, if necessary.] Wherein the central atom of the metal complex is an atomic number 27, 29-32, 37-39, 42
The method according to claim 1, wherein the method is a radionuclide of an element having an element having a length of from 51 to 62, 64, 70, 75, 77, 82, or 83. 5. The radioactive substance is a metal complex, the ligand of which is represented by the general formula II:[Where R⁹~ R²⁰Are equal or different and each is a hydrogen atom and / or unbranched or branched
, Cyclic or polycyclic C₁-C₁₀₀-Alkyl residue, -alkenyl residue, -A
Rukinyl residue, -aryl residue, -alkylaryl residue and / or aryl radical
Represents a alkyl residue, which, if necessary, is a fluorine atom, a chlorine atom,
Hydroxy containing iodine and / or iodine and / or up to 30 carbon atoms
Group, oxo group, carboxy group, aminocarbonyl group, alkoxycarbonyl group,
Substituted with an amino group, an aldehyde group or an alkoxy group and / or
, One or more of the sequences N, P, As, O, S, Se
Cleaved and / or substituted by a terrorist atom, and wherein the residue R¹¹And R¹², R ¹³ And R¹⁴, R^FifteenAnd R¹⁶And R¹⁷And R¹⁸Together, if necessary
And may represent an oxygen atom, and n, m and p are each independently 1 or
2]_TwoS_TwoDerivatives, and the central atom of the metal complex has an atomic number of 27, 29 to 32, 37 to 39, 42
Radionuclei of elements having ~ 51, 62, 64, 70, 75, 77, 82 or 83
3. The method according to claim 1, wherein the method is a seed. 6. The radioactive substance is a metal complex, the ligand of which is represented by the general formula III: Wherein R ^{21 to} R ³² are the same or different and each represents a hydrogen atom and / or an unbranched, branched, cyclic or polycyclic C ₁ -C ₁₀₀ -alkyl residue, -alkenyl residue. A radical, -alkynyl residue, -aryl residue, -alkylaryl residue and / or arylalkyl residue, which, if necessary, is a fluorine, chlorine, bromine and / or iodine atom A hydroxy group, oxo group, carboxy group, aminocarbonyl group, alkoxycarbonyl group containing atoms and / or up to 30 carbon atoms,
Substituted by an amino group, an aldehyde group or an alkoxy group and / or if necessary, cleaved and / or by one or more heteroatoms of the series N, P, As, O, S, Se. an N ₂ S ₂ derivative represented by the the] substituted, and the central atom of the metal complex, atomic number 27,29～32,37～39,42
The method according to claim 1, wherein the method is a radionuclide of an element having an element having a length of from 51 to 62, 64, 70, 75, 77, 82, or 83. 7. The metal complex used comprises a central atom, wherein the central atom is selected from the group of ^99m Tc, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁶⁷ Cu, ⁹⁰ Y and ¹⁰⁷ Ag. 7. The method according to claim 4, 5 or 6, wherein 8. The method according to claim 1, wherein the radioactive substance is a metal complex, and the ligand is a porphyrin derivative. 9. radioactive material, Method according to claim 1 or 2, characterized in that an isotope ²⁰¹ Tl, ²⁰⁷ Tl, thallium compounds of ²⁰⁹ Tl and ^{2 10} Tl. 10. The method according to claim 1, wherein the radioactive substance is ²⁰¹ TlCl. 11. The method according to claim 1, wherein the radioactive substance is a tetrofosmin derivative. 12. The method according to claim 1, wherein the radioactive substance is a sestamibi derivative. 13. The method according to claim 1, wherein the radioactive substance is a flifhosmin derivative. 14. The method according to claim 1, wherein the radioactive substance is a colloid solution having a particle size between 5 and 1000 nm. 15. The method according to claim 1, wherein the radioactive substance is ^99m Tc-tin colloid or ¹⁸⁶ Re-tin colloid. 16. The method according to claim 1, wherein the catheter used is a microporous balloon catheter. 17. The method according to claim 1, wherein the catheter used is a multi-lumen balloon catheter. 18. The ligand of the complex has the general formula I:[Wherein, when n = 0-3, the residue R¹~ R⁸Are equal or different and are each a hydrogen atom and / or
Is an unbranched, branched, cyclic or polycyclic C₁-C₁₀₀-Alkyl residue, -alke
Nyl residue, -alkynyl residue, -aryl residue, -alkylaryl residue and / or
Or an arylalkyl residue, which, if necessary, is a fluorine atom
, Chlorine, bromine and / or iodine and / or up to 30 carbon atoms
Including hydroxy group, oxo group, carboxy group, aminocarbonyl group, alkoxy
Substituted by a carbonyl, amino, aldehyde or alkoxy group, and
And / or, if necessary, one or more of the series N, P, As, O, S, Se
Is cleaved and / or substituted by further heteroatoms and wherein the residue R ^Two And R^Three, R^FourAnd R^FiveAnd R⁶And R⁷Together, if necessary
A bisamine oxime derivative represented by the formula: wherein the central atom of the metal complex is an atomic number
Radionuclide of an element having 51, 62, 64, 70, 75, 77, 82 or 83
For the manufacture of a medicament for topical administration in the treatment of a proliferative disease of a complex which is
use. 19. The ligand of the complex has the general formula II: Wherein R ⁹ -R ²⁰ are equal or different and are each a hydrogen atom and / or an unbranched, branched, cyclic or polycyclic C ₁ -C ₁₀₀ -alkyl residue, -alkenyl Residue, -alkynyl residue, -aryl residue, -alkylaryl residue and / or arylalkyl residue, which, if necessary, are a fluorine, chlorine, bromine and / or Substituted by an iodine atom and / or a hydroxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy group containing up to 30 carbon atoms, and / or
Or, if necessary, truncated and / or substituted by one or more heteroatoms of the series N, P, As, O, S, Se, and wherein residues R ¹¹ and R ¹² , R ¹³ and R ¹⁴ , R ¹⁵ and R ¹⁶ and R ¹⁷ and R ¹⁸ are, if necessary,
It may represent an oxygen atom together, and n, m and p are N ₂ S ₂ derivative represented by independently means 1 or 2], and is the central atom of the metal complex, atoms No. 27, 29-32, 37-39, 42
Use of a complex, which is a radionuclide of an element having -51, 62, 64, 70, 75, 77, 82 or 83, for the manufacture of a medicament for topical administration in the treatment of a proliferative disease. 20. The ligand of the complex has a general formula III: Wherein R ^{21 to} R ³² are the same or different and each represents a hydrogen atom and / or an unbranched, branched, cyclic or polycyclic C ₁ -C ₁₀₀ -alkyl residue, -alkenyl residue. A radical, -alkynyl residue, -aryl residue, -alkylaryl residue and / or arylalkyl residue, which, if necessary, is a fluorine, chlorine, bromine and / or iodine atom A hydroxy group, oxo group, carboxy group, aminocarbonyl group, alkoxycarbonyl group containing atoms and / or up to 30 carbon atoms,
Substituted by an amino group, an aldehyde group or an alkoxy group and / or if necessary, cleaved and / or by one or more heteroatoms of the series N, P, As, O, S, Se. an N ₂ S ₂ derivative represented by the the] substituted, and the central atom of the metal complex, atomic number 27,29～32,37～39,42
Use of a complex, which is a radionuclide of an element having -51, 62, 64, 70, 75, 77, 82 or 83, for the manufacture of a medicament for topical administration in the treatment of a proliferative disease. 21. The radionuclide is ^99m Tc, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁶⁷ Cu
, ⁹⁰ Y and ¹⁰⁷ Ag.
Use of a compound according to any one of 0. 22. In the manufacture of a medicament for treating a proliferative disease, the colloid solution comprises the elements Ag, As, At, Au, Ba, Bi, Br, C, Co, Cr, Cu,
F, Fe, Ga, Gd, Hg, Ho, I, In, Ir, Lu, Mn, N, O, P
, Pb, Pd, Pm, Re, Rh, Ru, Sb, Sc, Se, Sm, Sn, Tb
Use of a colloid solution characterized by being labeled with a radionuclide of T, Y or Tc. 23. The colloid solution ^{contains 99m} Tc, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁶⁷ C
^{u, 90 Y, 153 Sm,} 160 Tb, 162 Tb, 198 the use of a colloidal solution of claim 22, wherein in that it is labeled I by Au and ¹⁰⁷ Ag radionuclide selected from the group of. 24. The use of a colloid solution according to claim 22, wherein the colloid is produced by a redox reaction in the presence of a radioactive salt. 25. Use of a colloid solution according to claim 22, wherein the colloid is produced in an aqueous or alcoholic solution by changing the pH value in the presence of a radioactive salt. 26. Use of a colloidal solution according to claim 22, wherein the particle size of the colloidal particles is between 5 and 1000 nm. 27. Use of a colloid solution according to claim 22, wherein the particle size of the colloid particles is between 300 and 600 nm. 28. Use of a colloid solution according to claim 22, wherein the colloid solution is stabilized using a surfactant or another amphiphile. 29. Use of a radiolabeled sulfur colloid for the manufacture of a medicament for treating a proliferative disorder.