WO2006077166A1

WO2006077166A1 - Use of gallium (iii) complexes for treating tumours of the urothelial tract

Info

Publication number: WO2006077166A1
Application number: PCT/EP2006/000615
Authority: WO
Inventors: Bernhard Keppler
Original assignee: Faustus Forschung Translational Drug Development Ag
Priority date: 2005-01-24
Filing date: 2006-01-24
Publication date: 2006-07-27
Also published as: AT501262A4; AT501262B8; AT501262B1

Abstract

The invention relates to the use of gallium (III) complexes for treating tumours of the urothelial tract, such as e.g. carcinomas of the kidneys, renal pelvis, prostate and bladder and urethral tumours.

Description

Use of gallium (III) complexes for the treatment of tumors of the urothelial tract

The invention relates to the use of gallium (IH) complexes for the treatment of tumors of the urothelial tract.

It is known to use simple gallium salts such as gallium (III) chloride and gallium nitrate for the control of human tumors. For example, Collery US 4,596,710 describes the use of gallium chloride in the treatment of various human tumors. US Pat. No. 4,529,593 describes the use of inter alia gallium nitrate for the treatment of tumor-associated hypercalcemia. The treatment of tumors of the urothelial tract with gallium nitrate has also been described in the literature (Seligman et al, Proc. Annual Meeting Am Soc So Oncol, 1991, 10, A534, Crawford et al., Urology, 1991, 38 355-357, Seidman et Cancer 1991, 68, 2561-2565). In treating these tumors, particular emphasis has been placed on combination with other cytotoxic agents such as vinblastine and ifosfamide (Einhorn et al., J. Clin. Oncol., 1994, 12, 2271-2266, Dreicer et al., Cancer, 79, 1997) and gallium nitrate, respectively and 5-FU (McCaffrey, J. Clin. Oncol. 15, 1997, 2449-2455). A serious disadvantage of these small inorganic compounds is, on the one hand, the very limited bioavailability on the one hand when administered orally and the great nephrotoxicity, clinical use in humans (Krakoff et al., Cancer 44, 1722-1727, 1997; Senderowicz et al., Ural. int. 1999, 63, 120-125; Fagbemi et al., Seminars in Urology Oncology, 1998); 16, 23-29; Schwartz et al., Anticancer Res. 1984, 4, 317-318). In addition, weight loss, pneumonia and liver damage have also been observed with the use of simple gallium salts (Hart et al, J. Natl. Cancer Inst. 47, 1121-1127, 1971). Therefore, alternatives to the simple gallium salts gallium chloride and gallium nitrate were sought. One compound which avoids the above-mentioned disadvantages is gallium maltolate, which is currently in clinical trials (Lawrence Bernstein, WO 93/09776). This compound is characterized by a significantly increased bioavailability.

Gallium (III) complexes with nitrogen-containing ligands also show a much higher lipophilicity and improved bioavailability upon oral administration and have shown their antitumor activity in experimental animal tumors such as soft tissue sarcoma (Collery et al., WO 93/02087; Thiel et al., Relevance of Tumor Models for Anticancer Drug Development, Contrib. Oncol., Basel, Karger, 54, 439-442, 1999). Oral administration is particularly desirable for gallium compounds in the treatment of tumors, as these compounds should be given continuously over a longer period, as far as possible, due to the mechanism of ribonucleotide reductase inhibition.

In WO 02/074304, the use of gallium (III) complexes with nitrogen-containing ligands in combination with other therapeutically effective cytotoxic agents, e.g. various platinum (II) complexes described.

Surprisingly, it has now been found that gallium (III) complexes of the general formula (I), even without the combination with other cytotoxic compounds, are particularly suitable for use in the treatment of tumors of the urothelial tract. As before, the

Need for effective drugs for these indications great. In clinical

Studies have shown that gallium complexes of the general formula (I) in the treatment of these cancers a great

Own activity. Therefore, the invention has for its object to treat tumors of the urothelial tract.

This object is achieved by the use of a compound of general formula (I)

wherein R

is an N-containing group selected from a group of the general formula (II) to (VII):

(IV),

wherein

R ₁ Ci - C ₆ alkylene, C ₃ - C ₃ -cycloalkylene, C ₃ - C ₈ - cycloalkenylene, C ₂ - Ce alkenylene, a mono- or polynuclear, optionally aromatic, C ₆ - C ₄ ring system or a heterocycle, each of which may be substituted or unsubstituted is;

R ₂ and R _{3 is} C ₁ - Cio alkyl, C ₃ - C ₈ - cycloalkyl, C ₃ - C ₈ - cycloalkenyl, C ₂ - Cio-alkenyl, a mono- or mehrkemiges optionally aromatic, C ₆ - C ₁₄ - Ring system, or a heterocycle, which may each be substituted or unsubstituted, or is hydrogen; and Ri and R ₂ , or R ₁ and R ₃ , or R ₂ and R ₃ may form a heterocycle which may optionally contain further nitrogen atoms;

(VII)

wherein R _{4 has} the same meaning as Ri, R _{5 has} the same meaning as R ₂ , and

R ₄ and R ₅ together with N may form an optionally aromatic ring system which may contain further nitrogen atoms;

i is an integer from 0 to 3 and corresponds to the sum of the N-containing groups of the formulas (III) and / or (VI);

Y is a halogen, pseudohalogen, HCO ₃ or R ¹ COO, wherein R ^{1 is} C ₁ -

Is cycloalkenyl, aryl which may be substituted or unsubstituted, respectively, and / or a physiologically-acceptable anion C ₆ alkyl, C ₂ - C ₆ alkenyl, C ₃ - C ₆ cycloalkyl, C ₃ - - C _6; and

physiologically acceptable addition salts thereof,

Furthermore, it is preferred that the heterocycle for R _{1 is} a mononuclear or polynuclear basic heterocycle having one or more nitrogen atoms.

In a preferred embodiment, Ri is C ₁ - C ₆ alkylene, C ₃ - C ₆ -alkylene -Cycloal-, C ₃ - C ₆ -cycloalkenylene, C ₂ - C ₆ alkenylene, C ₆ - C ₁₄ - arylene or a heterocycle which may each be substituted or unsubstituted, and R ₂ and R ₃ Ci - C ₁₀ alkyl, C ₃ - C ₆ cycloalkyl, C ₃ - C ₆ cycloalkenyl, C ₂ - Cio-alkenyl, _C6 - Cu aryl, or heterocycle, each substituted or unsubstituted or hydrogen.

R ₁ is preferred:

C ₁ -C ₅ -alkylene, such as n-butylene or n-pentylene, in particular C ₁ -C ₃ -

Alkylene, such as methylene, ethylene, n-propylene or i-propylene;

C ₂ -C ₅ -alkenylene, such as butenylene or pentenylene, in particular C ₂ -C ₃

Alkenylene, such as ethenylene or propenylene; C ₃ -C ₆ -cycloalkylene, such as cyclopentylene or cyclohexylene, in particular C ₃ -C ₄ -cycloalkylene, such as cyclopropylene or cyclobutylene;

C ₃ -C ₆ -cycloalkylene, in particular C ₅ -C ₆ -cycloalkenylene, such as cyclopentenylene or cyclohexenylene;

C ₆ - do-arylene, in particular benzylene.

R ₂ and R ₃ are preferred:

C ₁ -C ₆ -alkyl, such as n-butyl, n-pentyl, or n-hexyl, in particular C ₁ -C ₃

Alkyl, such as methyl, ethyl, n-propyl or i-propyl;

C ₂ - Ce alkenyl, such as butenyl, pentenyl, in particular C ₂ - C ₃ alkenyl, such as ethenyl or propenyl;

C ₃ -C ₆ -cycloalkyl, such as cyclopentyl or cyclohexyl, in particular C ₃ -

C ₆ cycloalkyl, such as cyclopropyl or cyclobutyl;

C ₃ -C ₆ -cycloalkenyl, in particular C ₅ -C ₆ -cycloalkenyl, such as cyclopenttenyl or cyclohexenyl; C ₆ - C ₁₀ -aryl, in particular benzyl.

In a preferred embodiment, R ₄ and R _{5 form} an aromatic ring.

R ₁ , R ₂ and / or R ₃ are substituted in preferred embodiments by:

Hydroxyl, amino, -SO ₃ H, halogen, C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₃ -C ₆ -cycloalkyl, CyCe-cycloalkenyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ - AIkOXy-C ₁ -C ₄ alkylene, C _r C ₄ -Alkylmer- capto, alkylene -C ₄ alkylmercapto-Ci-C _4, alkylene CrC formyl, ₄ alkoxycarbonyl, Cr C ₄ alkoxycarbonyl-CrC _4, di-Ci -C alkyl-amino, di-Ci-C ₄ alkylamino-Ci- C ₄ alkylene, _di-Ci-C4 alkylaminocarbonyl, alkylene _{di-Ci-C4-alkylaminocarbonyl} CRC4.

Furthermore, groups of the general formula (II) are preferably selected from groups of the formulas (VIII) and (IX)

(VIII) (IX)

selected, where

R ₂ , R ₃ as defined above, R _{6 is} alkyl, cycloalkyl, aryl or heteroaryl, which may each be substituted or unsubstituted, p is 0 to 4, m, m 'is 0 to 2, especially 1.

Further, if p is 2, two ortho-substituents R _{6 may form} an optionally aromatic cycle.

R ₆ is substituted in preferred embodiments as defined above for Ri, R ₂ and / or R ₃ .

Groups of the general formula (III) are preferably selected from groups of the formulas (X) and (Xl)

(X) (XI)

selected, where

R ₂ , Rs, Re, P, m, m ^{1 are} as defined above.

Groups of the general formula (IV) are preferably from groups of the formulas

(XII) (XIII)

selected, where

R 2, R 3, R ₆ , P, m, m 'are as defined above.

Groups of the general formula (V) are preferably selected from the formulas (XIV) and (XV)

(XIV) ₁ (XV), in which

R _{6 is} as above, R _{1 is} alkyl, cycloalkyl, aryl or heteroaryl, which may each be substituted or unsubstituted,

Halogen, sulfonyl, q is 0 to 3, r is 0 to 2, and n is 0 to 2, especially 1,

selected.

Furthermore, if q or r is 2, two ortho substituents R _{6 may form} an optionally aromatic cycle.

Groups of the general formula (VI) are preferably selected from the formulas (XVI) and (XVII)

(XVI), (XVII)

in which

Re, R7, q, r, n are as defined above

selected.

Groups of the general formula (VII) are preferably selected from the formulas (XIII)

(XVIII) ₁ (XIX), wherein

R ₆ , R ₇ , q, r, n

as defined above,

selected.

In a further preferred embodiment, Y in the general formula (I) is chlorine. Particularly preferred are q and r = 0 in the groups of formulas (XIV), (XV), (XVI) ₁ (XVII), (XVIII) and (XIX).

With very particular preference R in the general formula (I) is a group of the formula (XV) and q = 0.

The invention also relates to the use of gallium (III) complexes of the general formula (I) for the preparation of a medicament for the treatment of tumors of the urothelial tract.

The tumors of the urothelial tract which are suitable for treatment by a gallium complex of the general formula (I) may be, for example, renal carcinomas, renal bovine carcinomas, carcinomas of the urether, prostate carcinomas, bladder carcinomas and metastases of these tumor entities in other organs. Testicular tumors and tumors of the penis can also be treated by the gallium complex according to the invention.

For the treatment of the aforementioned cancers, the gallium complex of the formula (I) is more preferably administered orally, but also intravenously, intramuscularly, intraperitoneally or subcutaneously. Also an external application is possible. Preferably, the administration is by peroral application.

The use according to the invention of gallium (III) complexes can be carried out in any suitable formulation, provided that the formation or maintenance of sufficient active ingredient levels is ensured. This can be achieved for example by oral or parenteral administration in appropriate doses. Advantageously, the pharmaceutical preparation of the active ingredient is in unit dose form adapted to the desired administration. A unit dose may be, for example, a tablet Dragee, a capsule, a suppository or a measured volume amount of a powder, a granulate, a solution, an emulsion or a suspension.

For the purposes of the present invention, "unit dose" is understood to mean a physically determined unit which contains an individual amount of the active ingredient in combination with a pharmaceutical carrier and whose active ingredient content corresponds to a fraction or multiple of a single therapeutic dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half, a third or a quarter daily dose. If only a fraction, such as one half or one quarter of the unit dose is needed for a single therapeutic administration, the unit dose is advantageously divisible, e.g. in the form of a tablet with a score.

The use according to the invention of gallium (III) complexes in a suitable drug, when carried out in unit doses and used for applications e.g. is determined in humans, with about 0.1 to 3000 mg, preferably 10 to 2000 mg and in particular 30 to 1500 mg of active ingredient. The drug can be administered once, but also continuously over a longer period of time. For oral treatment, similar dosages may be used.

The therapeutic use of gallium (III) complexes in a pharmaceutical composition according to the invention may take place 1 to 4 times a day at fixed or varying times, eg before meals and / or in the evening. However, it may be necessary to deviate from the stated dosages, depending on the type, body weight and age of the individuals to be treated, the nature and severity of the disease, the method of preparation and the application of the drugs, and the period or interval within which the Administration takes place. Thus, in some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases, the above-mentioned amount of active ingredient must be exceeded. It may also be useful to administer the drugs only once or at intervals of several days.

Determination of the required optimal dosage and mode of application of gallium (III) complexes may be made by any person skilled in the art on the basis of his or her knowledge.

The use of gallium (III) complexes according to the present invention may be in the form of drugs which typically comprise the gallium (III) complex and non-toxic pharmaceutically acceptable excipients which may be used as admixture or diluent, for example in solid, semisolid or liquid form or as a wrapping agent, for example in the form of a capsule, a tablet coating, a pouch or other container for the therapeutically active ingredient. A carrier can e.g. serve as a mediator for the ingestion of drug by the body, as a formulation aid, as a sweetener, as a flavoring, as a dye or as a preservative.

For oral administration, e.g. Tablets dragees, hard and soft capsules, e.g. from gelatin, dispersible powders, granules, aqueous and oily suspensions, emulsions, solutions or syrups.

Tablets may contain inert diluents, eg calcium carbonate, calcium phosphate, sodium phosphate or lactose; Granulating and distributing agents, for example maize starch, polyvinylpyrrolidone or alginates; Binders, eg starch, gelatin or acacia gum; and lubricants, for example, aluminum or magnesium stearate, talc or silicone oil. she may additionally be provided with a coating which may also be such as to cause a delayed dissolution and absorption of the drug preparation in the gastrointestinal tract, so that, for example, better tolerability, protease or retardation is achieved. Gelatin capsules may contain the drug mixed with a solid, eg calcium carbonate or kaolin, or an oily, eg olive, peanut, or paraffin oil, diluent.

Aqueous suspensions may contain suspending agents, e.g. Sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum or acacia gum; Dispersing and wetting agents, e.g. Polyoxyethylene stearate, heptadecaethylene oxycatanol, polyoxyethylene sorbitol monooleate or lecithin; Preservatives, e.g. Methyl or propyl hydroxybenzoates; Flavoring agents; Sweeteners, e.g. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup.

Oily suspensions may e.g. Peanut, olive, sesame, coconut or paraffin oil and thickening agents, e.g. Beeswax, hard paraffin or cetyl alcohol; furthermore sweeteners, flavorings and antioxidants.

Water-dispersible powders and granules may be used in the inventive use of gallium (III) complexes in admixture with dispersing, wetting and suspending agents, e.g. the above, as well as sweeteners, flavorings and colorants.

Emulsions may contain, for example, olive, peanut, or paraffin oil in addition to emulsifying agents such as acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweetening and flavoring agents. Aqueous solutions may contain preservatives, for example methyl or propyl hydroxybenzoates; Thickener; Flavoring agents;

Sweeteners, e.g. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup, as well as flavorings and colorants.

For parenteral administration of the drugs are sterile injectable aqueous solutions, isotonic saline or other solutions.

The invention will be explained below by way of examples. Examples

The activity of gallium (III) complexes for the treatment of tumors of the urothelial tract was investigated in a Phase I clinical study.

In this study, patients on 14 consecutive days received the active ingredient tris-hydroxyquinolinolato gallium (III) in the form of gastric juice-resistant tablets. Thereafter, the patients were observed for 14 days. Thereafter, the application cycle was repeated upon tumor response.

The following results were achieved:

PD = progressive; SD = stable; PR = Partial remission

Tris-hydroxyquinolinolato gallium (III) was found to be well tolerated in this study. The activity of the gallium compound in the indication renal tumor was observed in three patients with documented progression on entry into the study in the form of a stabilization in two cases or a partial response in one case. One patient was stable over a period of 36 weeks (patient 1).

Claims

claims

1. Use of a compound of the general formula (I)

wherein R

(IV),

wherein

Ri is C ₁ -C ₆ -alkylene, C ₃ -C ₈ -cycloalkylene, C ₃ -C ₈ -cycloalkylene, C ₂ -C ₆ -alkenylene, a mono- or polynuclear, optionally aromatic C ₆ -CH- ring system or Heterocycles which may each be substituted or unsubstituted;

R ₂ and R ₃ Ci - C ₁₀ alkyl, C ₃ - C ₈ - cycloalkyl, C ₃ - C ₈ - cycloalkanes -alkenyl, C ₂ - Cio-alkenyl, a mono- or polynuclear, optionally aromatic, C ₆ - C ₁₄ - Ring system, or a heterocycle, which may each be substituted or unsubstituted, or is hydrogen;

and Ri and R ₂ , or Ri and R ₃ , or R ₂ and R ₃ may form a heterocycle which may optionally contain further nitrogen atoms; R ₄ -N (V), - R ₄ -NH ⁺ (VI), and - R ₄ -NO ^" (VH)

R ₅ R ₅

R ₅

wherein

R _{4 has} the same meaning as Ri, R _{5 has} the same meaning as R ₂ , and

or

Y is a halogen, pseudohalogen, HCO ₃ or R ¹ COO, where R 'is Ci -

C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkenyl, aryl, each of which may be substituted or unsubstituted, and / or a physiologically acceptable anion; and

physiologically acceptable addition salts thereof,

for the treatment of tumor diseases of the urothelial tract.

2. Use of a compound according to claim 1, wherein R

(

is, where

R _{6 is} alkyl, cycloalkyl, aryl or heteroaryl, and P is 0 to 4.

3. Use of a compound according to claim 1, wherein R

is, where

Re is alkyl, cycloalkyl, aryl or heteroaryl, and P is 0 to 4.

4. Use of a compound according to claim 1, wherein R

is, where

R _{6 is} alkyl, cycloalkyl, aryl or heteroaryl, and P is 0 to 4.

5. Use of a compound according to any one of claims 2 to 4, wherein p = 0.

6. Use of a compound according to claim 1, wherein R

is, where

R _{6 is} alkyl, cycloalkyl, aryl or heteroaryl, and m, m 'are 0 to 2.

7. Use of a compound according to claim 1, wherein R

is, where

R _{6 is} alkyl, cycloalkyl, aryl or heteroaryl, and m, m 'are 0 to 2.

8. Use of a compound according to claim 1, wherein R

is, where

R _{6 is} alkyl, cycloalkyl, aryl or heteroaryl, and m, nϊ 0 to 2.

Use of a compound according to any one of claims 6 to 8, wherein m and m 'are 1.

10. Use of a compound according to claim 1, wherein R

is, where

R _{6 is} alkyl, cycloalkyl, aryl or heteroaryl, q is O to 3, r is O to 2, and n is O to 2.

11. Use of a compound according to claim 1, wherein R

is, where

12. Use of a compound according to claim 1, wherein R

is, where

13. Use of a compound according to any one of claims 10 to 12, wherein n is 1.

14. Use of a compound according to claim 1, wherein R

is, where

R _{7 is} alkyl, cycloalkyl, aryl or heteroaryl, which may each be substituted or unsubstituted, halogen, sulfonyl, and

q is 0 to 3.

15. Use of a compound according to claim 1, wherein R

is.

16. Use of a compound according to claim 1, wherein R

is.

17. Use of a compound according to claim 1, wherein R

is, where

R _{7 is} alkyl, cycloalkyl, aryl or heteroaryl, each of which may be substituted or unsubstituted, halogen, sulfonyl, and 0 to 3.

18. Use of a compound according to claim 1, wherein R

is.

19. Use of a compound according to claim 1, wherein R

is.

20. Use of a compound according to claim 1, wherein R

is, where

21. Use of a compound according to claim 1, wherein R

is.

22. Use of a compound according to claim 1, wherein R

is.

23. Use of a compound according to any one of claims 1 to 22, wherein Y is chlorine.

24. Use of a compound according to any one of claims 14, 17 or 20, wherein q is equal to zero.

25. Use of tris-hydroxyquinolinolato gallium (III) for the treatment of tumors of the urothelial tract.

26. Use of a compound according to any one of claims 1-25 for the treatment of renal carcinomas.

27. Use of a compound according to any one of claims 1-25 for the treatment of renal pelvic carcinomas.

28. Use of a compound according to any one of claims 1 -25 to

Treatment of prostate cancer.

29. Use of a compound according to any one of claims 1-25 for the treatment of bladder carcinomas.

30. Use of a compound according to any one of claims 1-25 for the treatment of tumors of the urether.

31. Use of a compound according to any one of claims 1-25 for the treatment of metastases of a tumor of urothelial origin.

32. A pharmaceutical composition containing a compound according to any one of claims 1 to 31.