WO1999011262A1 - Ligands du recepteur mpl, leur procede de preparation, medicaments les contenant et leur utilisation pour le traitement et la prevention de la thrombocytopenie et l'anemie - Google Patents

Ligands du recepteur mpl, leur procede de preparation, medicaments les contenant et leur utilisation pour le traitement et la prevention de la thrombocytopenie et l'anemie Download PDF

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Publication number
WO1999011262A1
WO1999011262A1 PCT/EP1998/005492 EP9805492W WO9911262A1 WO 1999011262 A1 WO1999011262 A1 WO 1999011262A1 EP 9805492 W EP9805492 W EP 9805492W WO 9911262 A1 WO9911262 A1 WO 9911262A1
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Prior art keywords
general formula
compounds
alkyl
phenyl
production
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PCT/EP1998/005492
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English (en)
Inventor
Michael Brandt
Hans-Willi Krell
Edgar Voss
Joachim Schmitt
Anne Stern
Johannes Auer
Manfred Kubbies
Albrecht Berkessel
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Roche Diagnostics Gmbh
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Application filed by Roche Diagnostics Gmbh filed Critical Roche Diagnostics Gmbh
Priority to AU92656/98A priority Critical patent/AU9265698A/en
Publication of WO1999011262A1 publication Critical patent/WO1999011262A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol

Definitions

  • the present invention is directed to metal complexes with Schiff base ligands, which contain sulfur, nitrogen or oxygen as donor atoms, have an agonistic and/or synergistic effect on the TPO receptor, methods of preparing same, and drugs containing same.
  • the invention relates to metal complexes of general formula I
  • Me represents cobalt, copper, nickel or zinc, which may optionally form a bond to N;
  • X represents sulfur, oxygen or an amino group which may be substituted by C_-C ⁇ o alkyl or benzyl;
  • Y represents oxygen, sulfur or an amino group which may be substituted by C_-C_o alkyl, benzyl or phenyl;
  • T represents nitrogen or CR 12 , wherein R 12 may be hydrogen,
  • L represents an ethylene group (A), an aromatic ring (B), or a heterocyclic ring (C):
  • R' R- independently represent hydrogen , C 1 -C 10 alkyl , phenyl , carboxyl , C 1 -C 10 alkoxycarbonyl , or amino carbon ⁇ yl .
  • R 3 R 6 , and R 7 independently represent hydrogen, chlo- rine , bromine, iodine. fluorine, trifluoromethyl, cyano , S0 3 H , S0 3 Na , -SO-R,9 9 , _ -_S,0« 2 _- ⁇ R_.9 9 , - nitro , phenyl which may optionally be substituted , C ⁇ -c ⁇ o alkyl ⁇ c ⁇ o alkoxy, c ⁇ c 10 acyloxy, aralkoxy, -C0-R 5 NR ⁇ R 11 hydroxy, or cycloalkyl; wherein
  • R 5 may be hydroxy, C ⁇ C- ⁇ alkyl, phenyl, amino, mono- or dialkylamino;
  • R 10 and R 11 independently represent hydrogen, C ⁇ -C ⁇ alkyl, phenyl, benzyl, or C ⁇ C ⁇ acyl;
  • R ⁇ R' together may form a carbocyclic saturated or unsatu ⁇ rated ring system having 5-14 C atoms, which may optionally have one or more substitutions by halogen, nitro, hydroxy, C ⁇ C- ⁇ alkyl, C ⁇ C ⁇ alkoxy, ⁇ C ⁇ alkoxycarbonyl, amino, sulfonyl, sulfinyl, mercapto, c ⁇ c i o alkylmercapto, mono- or di-Ci-Ci Q - lkylamino;
  • the invention is also directed to compounds of general formula II
  • R, R 1 , R 12 , Y, Z , L , and rr have the meanings specified for formula I , X represents sulfur , oxygen or an amino group which may be substituted by C ⁇ -C ⁇ alkyl or benzyl , and R represents hydrogen, benzyl , acetyl or C ⁇ C ⁇ alkyl , and their optically active forms , racemates , tautomers , diastereomeric mixtures , as well as the physiologically tolerable salts and prodrugs .
  • R, R 1 , L, Me, T, X, Y, and Z have the meanings specified for formula I
  • Q represents tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, ammonia, a primary, secondary or tertiary amine, pyridine, a trialkylphosphine or triphenylphosphine, l-Me-3 , 4-dihydroisoquinoline, 1,3, 3-trimerhyl-4-hydroisoquin- oline, and their optically active forms, racemates, tauto ⁇ mers, diastereomeric mixtures, as well as the physiologically tolerable salts and prodrugs .
  • Q may be a compound of general formula II, so that a complex is formed which contains metal ion and ligand at a ratio of 1:2.
  • Q may also be a compound of general formula I, so that a dimeric complex is formed which contains metal ion and ligand at a ratio of 1:1.
  • the invention also relates to methods of preparing the above compounds , drugs containing these compounds , and the use of these compounds in the production of drugs .
  • the compounds of general formula I, II or III have valuable pharmacological properties . They act as thrombopoi ⁇ etin agonists and/or synergists and thus, are suitable in the treatment of diseases where inter alia , thrombopoietin or other proteins/peptides binding to the mpl receptor (thrombo- poietin receptor) are used as therapeutic agents. In particular, they are suitable in the treatment of hematopoietic disorders, e.g., in the therapy of thrombopenias and anemias, e.g., following chemo- or radiotherapy or bone marrow transplantation, and in the mobilization of ste and progenitor cells.
  • TPO TPO
  • the megakaryocytes produced by progenitor cells are an important group. Megakaryocyte growth and development is controlled by hematopoietic growth factors. Thus, on the one hand, they effect expansion of the megakaryocyte progenitors (megakaryopoiesis) and, on the other hand, induce megakaryocyte maturing up to formation of thrombocytes (thrombopoiesis) .
  • thrombopoiesis thrombopoiesis
  • Thrombocytes also referred to as blood platelets, are small cells which contribute to blood clotting, and close wounds as a result of their ability of aggregating. Following fragmentation of the cytoplasm, megakaryocytes release blood platelets into the vascular space. In a healthy person, 3-10 billion thrombocytes are produced by the blood-generating cells of the bone marrow.
  • TPO thrombopoietin
  • M-GDF megakaryocyte growth and development factor
  • TPO In addition to its effect on egakaryopoiesis, TPO also stimulates erythropoiesis [5] and therefore, also increases formation of erythrocytes in myeio-suppressed, irradiated mice which had been treated with a chemotherapeutic agent. Moreover, it has been possible to achieve a raise in neutrophiles [5]. Similarly as in animal models, TPO effects an increase of blood platelets in tumor patients with thrombopenia [6,7] and exhibits good tolerability (WO-A- 96/15758, WO-A-97/16535) .
  • TPO human protein Treatment using TPO human protein involves a number of drawbacks: Being a recombinant protein, it is extremely expensive, it has to be administered on the parenteral route due to lacking oral bioavailability, and it is liable to rapid degradation by proteases to form inactive fragments .
  • WO-A-96/40750 describes peptides having TPO-agonistic activity, but in this case as well , there is the same problem of lacking oral bioavailability and sensitivity to proteases , making it necessary to administer these substances by injection or infusion .
  • C ⁇ C ⁇ alkyl in all cases represents a straight or branched C ⁇ C- ⁇ chain which may optionally have one or more substitutions by C ⁇ C ⁇ alkyl or hydroxy, with methyl , ethyl , propyl , i-propyl, n-butyl , tert-butyl , pentyl , hexyl , heptyl , octyl , nonyl , or decyl groups being preferred.
  • the C ⁇ C ⁇ alkoxy groups in the compounds of formula I , II or III contain straight or branched c i" ⁇ o alkyl chains , with methoxy, ethoxy, n-propyloxy, i-pro- pyloxy, n-butyloxy, tert-butyloxy, pentyloxy, hexyloxy, hep- tyloxy, octyloxy, nonyloxy, or decyloxy groups being preferred.
  • the C ⁇ C- ⁇ acyl residue is understood to be a formyl, acetyl, propanoyl, butanoyl, pentanoyl, hexano- yl, heptanoyl, octanoyl, nonanoyl, or decanoyl residue.
  • the aralkyloxy groups contain a phenyl group linked with a C- L -C- LQ alkoxy group, the benzyloxy, phenylmethoxy and phenylethoxy groups being preferred.
  • the carbocyclic saturated or unsaturated ring systems having 5-14 C atoms, which are formed by R 1 and R 7 together and may optionally have one or more substitutions, are understood to be cyclopentane, cyclohexane or indane, for example, with cyclopentane and indane being preferred.
  • R 4 , R 5 , R 6 , or R 7 in the compounds of general formula I, II or III is a cycloalkyl group, it is understood to be a ring having from three to six carbon atoms.
  • the substituents o£ a carbo- or heterocyclic saturated or unsaturated ring system are understood to be halogen, nitro, cyano, hydroxy, ⁇ -C ⁇ alkyl, C 1 -C 10 alkoxy, C ⁇ C ⁇ alkoxycarbonyl, amino, C 1 -C 10 alkylsulfonyi, C ⁇ -C 1Q alkylsulf- inyl, mercapto, C 1 -C 10 alkylmercapto, mono- or di-C ⁇ C ⁇ - alkyla ino, or trifluoromethyl.
  • Those compounds of general formula I, II or III are particularly preferred wherein Me represents nickel, R 1 is hydrogen, L represents the group (B), Q is ammonia in the case of formula III, and R 4 , R 5 , R 5 , and R 7 independently represent hydrogen, C 1 -C 10 alkoxy, C ⁇ C- ⁇ acylamino, benzyloxy, C 1 -C 10 monoalkylamino, amino, di-C 1 -C 10 -alkylamino, or halogen, S0 3 Na, or S0 3 H, or R 4 and R 6 at the same time represent halogen; it is particularly preferred that halogen represents chlorine or bromine, X is oxygen, T is nitrogen, Z is NH, and Y represents oxygen or sulfur.
  • Prodrugs are understood to be compounds which are metabolized in vivo to give compounds of general formula I, II or III.
  • physiologically usable salts of the compound of formula I are salts with physiologically tolerable mineral acids such as hydrochloric acid, sulfuric acid, sul- furous acid or phosphoric acid, or with organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, or salicylic acid.
  • Compounds of formula I having a free carboxyl group may also form salts with physiologically tolerable bases . Examples of these salts are alkali metal, alkaline earth metal, ammonium, and alkyl- ammonium salts, such as sodium, potassium, calcium, or tetra- methylammonium salts.
  • the pure enantiomers of the compounds of formula I, II or III are obtained either by resolving the racemates (via salt formation with optically active acids or bases) or by using optically active starting materials in the synthesis.
  • Zh. Obshch. Khim. 60, 2549 (1990) describes the preparation of compounds of general formula III, wherein Q represents pyridine, aniline or an aliphatic amine.
  • Compounds of general formula III may be used as catalysts in the reduction of i ines , and such a use does not have any relation to the activity as a TPO agonist which has been found.
  • the EP-A- 168,343 describes the use of compounds of general formula I for dyeing plastics .
  • the preparation of compounds of general formula III, wherein Q represents a ligand containing nitrogen such as ammonia or a pyridine derivative has been described in Issled. Khim. Khelatnykh Soedin. 3, (1971).
  • the compounds of general formula II are prepared by condensation of the corresponding aldehydes or ketones with the corresponding hydrazine derivatives or amine derivatives (e.g., Acta Chem. Scand. 15, 1097 (1961)).
  • the complex compounds of general formula I and III are obtained in a per se known manner by contacting the ligands with the corresponding metal acetates and heating in methanol (Zh. Neorg. Khim. 32, 1158 (1987); Zh. Obshch. Khim. 60, 2549 (1990)).
  • the substances of general formula I, II or III are mixed with suitable pharmaceuti- cal vehicles, flavoring substances, taste improvers, and colorants and formed into tablets or coated tablets, or suspended in water or oil, e.g., olive oil, with addition of appropriate adjuvants.
  • the compounds of general formula I, II or III and their salts may be applied in liquid or solid form on the enteral or parenteral route.
  • Water is preferably used as injection medium, containing stabilizers, solubilizers and/or buffers usual in injection solutions.
  • such additives are tartrate or borate buffers, ethanol, dimethyl sulfoxide, chelating agents (such as ethylenediaminetetra- acetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity control, or polyethylene derivatives of sorbitol anhydrides.
  • solid vehicles are starch, lactose, mannitol, methylcellulose, talc, highly disperse silicic acid, higher molecular weight polymers (such as polyethylene glycols).
  • taste improvers and sweeteners may additionally be contained, if desired.
  • the dosage administered will depend on the age, the TPO level present in the patient, health condition, weight, extent of disease, the type of other treatments possibly conducted at the same time, and the type of effect desired.
  • the daily dose of active compound will be from 0.01 to 5 mg/kg body weight.
  • Example 1 The invention will be exemplified by the following examples, without being limited thereto.
  • Example 1 The invention will be exemplified by the following examples, without being limited thereto.
  • Example 1 Example 1 :
  • N'-( 2-hydroxybenzylidene)thio- benzoic acid hydrazide 81 was dissolved in 30 ml of boiling methanol.
  • a solution of 0.24 g (0.975 mmol) of nickel (II) acetate tetrahydrate in 15 ml of methanol heated to 60 °C was added with stirring. After a few minutes, the beige-brown metal complex began to precipitate. For complete precipitation, a standing period of 24 hours at room temperature was allowed. The metal complex was subsequently sucked off and washed with methanol and distilled water.
  • the compounds of general formula II are prepared by condensation of the corresponding aldehydes or ketones with the corresponding hydrazine derivatives (e.g., Acta Chem. Scand. 15, 1097 (1961)).
  • the bioactivity of the compounds according to the invention may be measured using a TPO-dependent cell proliferation test.
  • the substances may not exert any effect on non- transfected parent BaF3 cells.
  • Murine BaF3 cells with IL-3- dependent growth [8] were transfected with human mpl receptor. In the absence of IL-3, proliferation and survival of these cells depend on TPO ( Figure 1).
  • the non-transfected parent cell line does not respond to human TPO, yet proliferates in the presence of IL-3.
  • the cell proliferation is determined according to methods well-known in literature (WO 96/40750). The libraries of chemical substances were screened in bioassays using the two cell lines above.
  • FCS fetal calf serum
  • the cells were washed twice in a medium free of IL-3 and TPO, respectively, and resuspended in a medium containing no TPO and IL-3, respectively.
  • the cell suspension was then added in an amount of 10 4 cells/well to the wells of a 96 micro-well plate (Costar), which contained TPO or IL-3 and/or the compound.
  • the cells were then incubated in a C0 2 incubator for 48-72 hours at 37°C.
  • the proliferative activity was determined by addition of WST (WST: cell proliferation reagent; BM catalog No. 1644807 “Tetrazolium Salz”). WST is converted to formazan by proliferative cells, and this conversion as a measure for proliferation is determined using the OD (OD: optical density) at 570 nm in an ELISA plate measuring instrument.
  • WST cell proliferation reagent
  • BM catalog No. 1644807 “Tetrazolium Salz”
  • the background (cells with no substance) was subtracted from the maximum signal achieved, and this value was divided by 2. This value plus background value was then used to determine the EC 50 (half maximum excitatory concentration: substrate concentration where the substance has half the maximum activ- ity in the BaF3/mpl receptor proliferation test).
  • Table 5 exemplifies the EC 50 values for two tested compounds .
  • the tested compounds stimulate proliferation of BaF3 cells transfected with mpl receptor in a dosage-dependent fashion. Proliferation of parent cell lines is not stimulated. Even in the absence of TPO, the compounds stimulate proliferation of the BaF3/mpl cells in a culture over weeks.

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Abstract

La présente invention porte sur l'utilisation de complexes métalliques de la formule générale (I) avec des ligands de base de Schiff contenant du soufre, de l'azote et de l'oxygène comme atomes donneurs, et ayant à la fois un effet agoniste et synergique sur le récepteur TPO dans le traitement de pathologies ou de troubles dans lesquels on utilise la thrombopoïétine ou une autre liaison peptide/oxygène au récepteur mpl comme agent thérapeutique, notamment dans le traitement des thrombopénies et des anémies. L'invention porte également sur les médicaments que contiennent ces complexes dans lesquels L, X, Me, Y, Z, R, et R1 sont tels que spécifiés.
PCT/EP1998/005492 1997-09-02 1998-08-29 Ligands du recepteur mpl, leur procede de preparation, medicaments les contenant et leur utilisation pour le traitement et la prevention de la thrombocytopenie et l'anemie WO1999011262A1 (fr)

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AU92656/98A AU9265698A (en) 1997-09-02 1998-08-29 Mpl-receptor ligands, process for their preparation, medicaments containing themand their use for the treatment and prevention of thrombocytopaenia and anaemia

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EP97115161.8 1997-09-02
EP97115161 1997-09-02

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WO2002049413A2 (fr) * 2000-12-19 2002-06-27 Smithkline Beecham Corporation Mimetiques de thrombopoietine
US6413952B1 (en) 1997-10-31 2002-07-02 Smithkline Beecham Corporation Agonizing dimeric cell-surface receptors with a receptor binding moiety and chelating metal
WO2002070464A2 (fr) * 2001-01-22 2002-09-12 Arpida Ag Nouvelles hydrazones
US6498155B1 (en) 1998-11-17 2002-12-24 Smithkline Beecham Corporation Methods of treating thrombocytopenia
US6720345B1 (en) 1999-11-05 2004-04-13 Smithkline Beecham Corporation Semicarbazone derivatives and their use as thrombopoietin mimetics
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