Trehplastinnaya complexes of pt(ii), the method of production thereof

 

(57) Abstract:

Proposed trehplastinnaya complexes of Pt (II) General formula (I), where X, Y, Z, and T is neutral and/or anionic ligands, which may be the same or different, provided that at least one of X, Y or Z each PT (b) must be anionic ligand; And includes diamino bridge agent-NH2- (CH2)s- NH2-; n - the total charge trehmetrovyh coordination spheres; R is one or more counterions, which may be present or not be present depending on whether have or not have three platinum coordination sphere of total charge, m = 0-2 is the number of counterions. Proposed also a method of obtaining trehmetrovyh complexes. Trehplastinnaya complexes in the present invention due to their content of three platinum coordination spheres provide enhanced cytotoxic activity in comparison with the currently used mono - and besplatnye complexes. 2 S. and 9 C.p. f-crystals, 2 PL.

The invention relates to new trehlitrovy complexes, processes for their preparation and their use as pharmaceuticals, in particular for the treatment of cancer.

Prepos the latin/ carboplatin /carboplatin/ chemotherapie cancer is well known to specialists. Some platinum complexes, such as platinol is a registered trademark of cisplatin, manufactured by Bristol Myers, Co. used to treat testicular, ovarian carcinoma, carcinoma of the head and neck, and small cell lung cancer. However, treatment with cisplatin can lead to severe nephrotoxicity. Other clinical disadvantage is the problem of acquisition of resistance to medicinal drug, resulting in the fact that the tumor becomes resistant to the action of the tool.

To overcome the nephrotoxic effect of cisplatin developed an analogue of the second generation - carboplatin. Paraplatin is a registered trademark of carboplatin produced by Bristol Myers, Co. Carboplatin, or [Pt(NH3)2(CBDCA)] (where CBDA is a 1,1'-cyclobutanedicarboxylate), is effective against the same spectrum of carcinomas, and cisplatin, but shows a significant decrease in nephrotoxic effects.

Developed a number of different platinum compounds intended for the treatment of various tumors or carcinoma. For example, U.S. patent N 4225529 discloses the use of CIS-coordination platinum derivative with four new or different amines with a linear chain, with which the platinum atom forms a coordination bond through their nitrogen atoms. Such complexes are used for the treatment of leukemia L-1210 in mice.

The U.S. patents NN 4250189, 4553502 and 4565884 refer to different complexes of Pt(II) and Pt(IV) with antitumor activity. Such besplatnuyu complexes associated with carboxylate connection so that upon introduction of such complexes patient complexes undergo rapid hydrolysis with the formation of two CIS-monoplatinum particles, which are then delivered to the active site.

In addition, U.S. patent N 4797393 describes besplatnuyu complex, which is delivered to the active site intact. This besplatnuyu complex has bridged diamines or polyamines ligand and contains a primary or secondary amines or azoty pyridine species associated with platinum complex, as well as two different or identical ligand, which can be a halide, sulfate, phosphate, nitrate, carboxylate, or, in primary forms. In addition, the registered application N 07/713105 refers to besplatnuyu complexes, in which besplatnuyu part linked diamines bridge, and in which the platinum radicals associated with ionic or ="ptx2">

However, there are still critical points that limit the effective use of platinum complexes as therapeutic agents, and most are their narrow spectrum of activity against various tumors and tumor cells that are resistant to the cytotoxic action of cisplatin. /Loehrer et al., Ann. Intern. Med. (1984), 100, 704 - 711/. An overview of existing platinum analogues, see Christian, Michael, Seminars in Oncology, 1992, 19, 720 - 733.

In General I believe that the platinum complexes such as cisplatin, exert their biological activity through covalent interaction with DNA. In particular, cisplatin induces the formation of a number of adducts on DNA, including monodentate adducts, bidentate adducts such as GG or AG, and vnutrisnih cross-linking GNG. /Reedijk et al., Structure and Bonding(1987), 67, 53 - 89/. To a lesser extent cisplatin also produces cross-links cross-links GG and cross-links DNA-protein. /Rahmauni et al., Biochemistry, (1987), 26, 7229 - 7234/. Such DNA damage give conformational changes, which are reflected in the collapse and the unwinding of the DNA. It is reported that such DNA damage inhibit the activity of various DNA polymerases. /Vallan et al., Nucl. Acids Res. (1988), 16, 4407 - 4418; Pinto et al., Proc. Natl goinnovate grounds inhibits the function of RNA polymerase. /Lemaire et al., Proc. Natl. Acad. Sci. (1991), 88, 1982 - 1985/. Accordingly, the cytotoxic action of cisplatin is the most similar to the joint effects of such separate DNA damage, and is not the result of any one specific case of damage.

In the technique known monoplatinum and besplatnuyu complexes containing one or two atoms of platinum. (See, for example, the U.S. patents NN 4225529, 4250189, 4533502, 4565854, 4571335 and 4797393/. For example, monoplatinum complexes include Monomeric square planar compounds of bleach and Pt(II), which consists of four coordination bonds. The relative number of chloride groups ammonia in such compounds may vary, and such compounds can therefore be described by the General formula

[PtClm(NH3)4-m](2-m)+.

Thus, the structure of these compounds can vary from [Pt(NH3)4]2+where m = 0 to PtCl42-where m = 4. Because Cl is more fluid Deputy in comparison with ammonia complexes [PtCl2(NH3)2] and [PtCl(NH3)3] Cl are considered as bifunctional and monofunctional, respectively, where the prefixes bi - and mono - are among arseplay the charge neutralization is required negative charge of -2. For example, when m = 0, neutralization is provided by the presence of two chlorine anions.

Education coordination leads to the formation of electron pairs in connection Pt-Cl. However, since it is believed that the ammonia ligand is neutral, the relationship can be described as transmission electron pair from the NH3to the vacant orbital of the atom Pt(II). Thus, the socialization of electron pairs between Pt and the group of NH3does not occur. Since the collectivization of electron pair is missing, the number of neutral ligands does not affect the overall charge of the coordination sphere Pt. Thus, [Pt(NH3)4]2+formally, is a 2+ cation, requiring necoordonarea anion or anions, or contrarians with a full negative charge 2 - for neutralization of the complex. For example, the neutralization can be achieved in two odourization charged anions (e.g., NO3-, Cl-PF6-BF4-and monocarboxylate having the General formula RCOO-or one dualization charged anion (e.g., SO42-dicarboxylate having the General formula (RCOO)22-). Therefore, the same considerations, [PtCl2(NH3)23)4]2+[PtCl4]2-.

It is noted that anionic ligands, such as Cl-can be either connected coordinating /i.e. forming a connection Pt - Cl/ or can act as contrarian without any need for the formation of covalent bonds. The exact form in which anions, such as Cl-included in this platinum complex, depends both on theoretical considerations /kinetic effects against thermodynamic/, and the actual methods of synthesis used for more complex /for example, the order of the reaction, the acidity, the concentration of a specific anion, e.g., the concentration of Cl-that is contained in the reaction mixture/. Similar considerations apply also for other anions and neutral ligands.

Examples of neutral ligands, usually included in monoplatinum complexes are, for example, olefins such as ethylene (C2H4), propene and 2-butene; phosphines (PR3), sulfides (SR2), sulfoxidov (R2SO), ammonia (NH3), primary amines (RNH2) and heterocyclic amines, such as pyridine or quinoline. Examples of typical anionic ligands, sohaney, such as SCN-CN-, NO3-. The term "pseudohalogen" includes the definition of which is given on page 560 in "Advanced Inorganic Chemistry, Cotton and Wilkinson. Other suitable pseudohalogen can be found in many well-known books on inorganic chemistry, for example, in Inorganic Chemistry, Cotton and Wilkinson.

The fact that the total charge monoplatinum complexes depends on the relative number of neutral and anionic ligands, which are connected with metal Pt(II), for example, NH3-and Cl--ligands, is applicable to polynuclear complexes which contain more than one coordination sphere of Pt(II)/ and complexes containing Pt(IV), in which the oxidation state of platinum is 4+. For example, dual core complexes, in which two equivalent coordination of Pt(II) contact diamines bridge, can be represented by the General formula [{PtClm(NH3)3-m}2(diamine)]2(2-m)+. Thus, when m = 2 and there are two bifunctional coordination sphere, the compound is neutral. In contrast, when m = 1, there are only uni-functional coordination, and Pt part has a formal charge of 2+, which must be balanced by one or nickoley and besplatnuyu complexes and their use as anti-cancer therapeutics.

In contrast, the present invention describes the synthesis trehmetrovyh complexes containing three platinum coordination sphere, where the platinum atoms are linked diamines and triamine bridging agents. The type of bridging agent may be selected so as to obtain a linear or "curved" ("bent") tributemovies links. Due to the presence of three platinum atoms introduction of such complexes should create the opportunity to deliver three cisplatinum links or platinum amine units in the same region of DNA, a property that does not have the usual monoplatinum or rioplatense complexes. Accordingly trehplastinnaya complexes should provide increased formation of DNA adduct compared with monoplatinum and besplatnye complexes and subsequently should lead to enhanced cytotoxic effect, as I believe that the minimum education bifunctional adduct DNA is the mechanism by which platinum complexes mediate cytotoxicity.

In the most General terms, the object of the present invention is trehplastinnaya complexes in which three platinum coordination spheres are linked with a diamine of the t 2+ or 4+, or is a combination thereof.

Another object of the invention are pharmaceutical compositions containing trehplastinnaya complexes, in which the platinum coordination sphere linked diamines or triamine bridging agents.

Another object of the present invention is the method of synthesis trehmetrovyh complexes, in which the platinum coordination sphere contact diamines or triamine bridging agents.

A specific object of the invention is trehplastinnaya complexes of Pt(II), General formula

< / BR>
< / BR>
where X, Y, Z and T are neutral or anionic ligands, which may be the same or different provided that at least one of X, Y or Z each Pt(b) must be anionic ligand; A comprises diamines or triamines bridging agent, n represents the total charge three platinum coordination spheres, P represents one or more contrarians, which can be used depending on, have or do not have three platinum coordination sphere full charge and n represents the total charge of contrarians /if they are/ where the number and charge of such contrarians select the I am trehplastinnaya complexes, where platinum components exist in oxidation States of Pt(IV), or combinations of States of oxidation of Pt(II) and Pt(IV). Specifically, such trehplastinnaya complexes will be presented formulas

< / BR>
in which X, Y, Z, A, and T described above, and where the group V are anionic groups, preferably (OH)-, (Cl)- or O2CR.

Complexes of Pt(IV) known in the art. For example, tetraploid /ormaplatin/, CIS-/PtC4-(dach)/ and CHIP, CIS-, CIS-TRANS-[PtCl2(ISO-PtNH2)2(OH)2] are examples of complexes of Pt(IV), which are known. For example, the oxidation of platinum to form Pt(IV) is usually achieved by treating H2O2and/or Cl2. For example, CIS-[PtCl2(NH3)2] or H2O2and/or Cl2as the oxidizing agent gives CIS-, CIS-TRANS-[PtCl2(NH3)V2], where V = OH, Cl. Specialists in the art it will be clear that when V = OH, you can carry out the replacement of the OH group of the carboxylate with obtaining V = O2CR, where R can be a linear or branched alkyl or alkenylphenol group, preferably -(C1-C18)-; aromatic group or aracelio group. In the technique, as a rule, it is recognized that to the AK and trehmetrovyh complexes of formulas (I), (II) and (III), in trehmetrovyh complexes of Pt(IV) P is contrarian or contrarian, which may be the same or different, m represents the number of such counter-ions and n represents the total charge of such contrarians and is such that the resulting trehlitrovy complex was neutral. When three platinum components have full neutral charge, contrarian will not be present.

Another specific object of the invention are pharmaceutical compositions containing at least one trehlitrovy complex of formula (I), (II), (III), (IV), (V) or (VI).

Another object of the invention is the method of application trehmetrovyh complexes of formulas (I), (II), (III), (IV), (V), (VI) for therapeutic applications, for example, for the treatment of tumors or parasitic conditions.

Another object of the present invention is the method of synthesis trehmetrovyh complexes of General formulas (I), (II) or (III). Another specific object of the invention are methods of synthesis trehmetrovyh complexes of the General formula (IV), (V) or (IV), in which educated charge platinum cations included in them, is 4+, or a combination of oxidation States 4+ and must provide an enhanced cytotoxic activity in comparison with the currently used mono - and besplatnye complexes.

Detailed description of the invention.

The present invention relates to a new class of trehmetrovyh complexes, which should be enhanced cytotoxic activity in comparison with the currently used platinum complexes. In particular, such trehplastinnaya complexes will be presented to the General formula:

< / BR>
in which X, Y, Z and T are neutral and/or anionic ligands, provided that at least one of X, Y or Z each Pt(b) must be anionic ligand; A comprises diamines or triamines bridging agent, n includes a full charge in three platinum coordination spheres; P, if required, includes one or more contrarians, which may be the same or different; m represents the number of such contrarians and n means the total negative charge of contrarians that selected so to the total charge trehmetrovogo complex is zero. In trehmetrovyh complexes of formula (IV), (V) or (VI) V means a monovalent anionic group, such as halide ion, pseudohalogen-ion, carboxylate, hydroxide. Preferably, the anionic group will represent the (OH)-, (Cl)-or O2CR.

Preferred is x amines, secondary amines, heterocyclic amines, sulfoxidov (R R SO), and anionic ligands, preferably will be selected from the group consisting of halides, pseudohalogen (where "pseudohalogen" included in the definition given on page 560 in "Advanced Inorganic Chemistry, Cotton and Wilkinson), carboxylates, monovalent anions, such as PF6-BF4-, anionic ligands and divalent anions such as SO4-2. As noted, at least one of X, Y or Z on each Pt(b) will be an anionic ligand, preferably a chloride group.

Primary amines included in trehplastinnaya complexes, will cover, preferably, the bonds alkylamines of the formula NH2-R1where R1means linear or branched (C1-C8)-alkyl group, or (C3-C6)-cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or will be a group-CH2OH.

Secondary amines, acceptable as a neutral ligands discussed in trehmetrovyh complexes will include, preferably, bonds alkylamines of General formula NH(R1)2where R1again includes, preferably, (C1-C8)-alkyl Lee is, cyclopentyl, cyclohexyl or a group CH2OH.

The sulfoxidov R R"SO that suitable as neutral ligands discussed in trehmetrovyh complexes, include any combination of the groups R' and R", where R' and R" include alkyl or aromatic group, preferably, - Me, Ph-X-Ph /where X may represent, for example, halide, methoxy group or hydroxyl group/ CH2Ph, Et, n-propyl, isopropyl or n-butyl.

Suitable heterocyclic amines suitable as a neutral ligand to discuss trehmetrovyh compounds include, for example, compounds having a saturated or unsaturated heterocyclic ring, such as pyridine, quinoline, isoquinoline, imidazole, thiazole, substituted pyridine, substituted quinoline, substituted thiazole, piperidine, pyrrolidone, morpholine and N-alkyl - or N-acyl-piperazine.

Anionic ligands suitable for use in the present trehmetrovyh complexes include, for example, halides, pseudohalogen, carboxylates and one - and divalent anions. Preferably, anionic ligands include halides, and most preferably, chloride. However, other halides, such as bromides and iodides can also nowych complexes according to the invention, will include, for example, SCN-CN-, NO3-or any of pseudohalogens mentioned in well-known books on chemistry, such as "Advanced Inorganic Chemistry, Cotton and Wilkinson". Typical examples of carboxylate groups, which can be used in discussing trehmetrovyh complexes include, for example, acetate, propionate, butyrate, CHLOROACETATE, hydroxyacetate, benzoate, and hepatoblastoma dicarboxylate groups, such as oxalat, malonate, substituted malonate, succinate, glutarate and phthalate.

Preferably such substituted malonate group will have a General formula

< / BR>
where R3are the same or different and include, for example, hydrogen (provided that both R3cannot be hydrogens), (C1-C8)-alkyl, linear or branched groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, or both groups together -(R3)2- represent (C3-C6-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a group-CH2OH.

As noted, A in the above formula includes forming bridges diamines or triamine. Such obrazu, preferably, a linear or branched alkyl or alkenylphenol group, preferably -(C1-C18), including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-octyl, oleyl, linoleyl; cycloalkyl group, preferably -(C3-C6-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; substituted phenyl, such as ortho-, meta - or paratool, mono - or dehalogenation phenyl groups, preferably chlorine, bromine or fluorine; mono - and dimethoxysilane phenyl group; kalkilya group, preferably -(C7-C10)-kalkilya groups, such as phenylmethyl, phenylethyl and phenylpropyl; and performanceline groups such as trifluoromethyl and triptorelin.

Preferred bridging diamine A will be covered by the General formula

NH2-(CH2)q-R2-(CH2)r-(R)NH,

in which R includes the above-mentioned group, and q and r are integers, which may be the same or different, and are in the range from 1 to 4 inclusive, and R2choose preferably the following groups: -CH2-, -CHOH-, -CO-, -CHOR-, OC(O)(O), -SO2>-(CH2)s-NH2where s is an integer in the range from 2 to 9, inclusive.

Criminaly bridging agent, preferably, will be represented by the General formula

< / BR>
where R, R' and R" may be the same or different and may represent a linear or branched alkyl or alkeneamine group, cycloalkyl, aralkyl, perftoralkil and aromatic groups. Preferably, R, R' and R" will be (C1-C18)-alkyl or alkenylamine linear or branched groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-octyl, oleyl, linoleyl; cycloalkenyl groups, preferably -(C3-C6)-cycloalkenyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; substituted fenelli, such as ortho-, meta-, or para-tolyl, mono - or dehalogenation phenyl group and dimethoxysilane phenyl group; Uralkalij groups, preferably - (C7-C10)-Uralkalij groups, such as phenylmethyl, phenylethyl, and phenylpropyl; and performanceline groups such as trifluoromethyl and triptorelin. In the most preferred implementation the bridging agents, having a "curved" refers to trehlitrovy complexes having the General structure represented by formula (III).

As noted earlier, P includes one or more contrarians that can be present or not be present, depending on whether have or not have three platinum coordination sphere of total charge. The number of such contrarians means "m", which will usually be from 0 to 4 inclusive. The value of the charge of such contrarians will be such that the total charge trehmetrovogo complex is zero. Examples of suitable contrasinal include, for example, halides, including Br-, Cl-and I-and other anionic ligands, such as NO3-, SO42-, ClO4-, carboxylates, such as mono - and dicarboxylate listed above, and PF6-and SbF6-. This list is indicative and not exhaustive.

Trehplastinnaya complexes, referred to, are synthesized, preferably, three-stage method.

To link the two platinum coordination sphere of a certain stereospecific manner, it is necessary, first, to obtain a monomer precursors is zakompleksovanniy end, which contains a protective agent /for example, SIDE, tetramethoxysilane/ or salt NH3+. Subsequent reaction with a suitable target gives dual core samples:

< / BR>
On the contrary, when you get discussed trehplastinnaya complexes containing three CIS-Pt(amine)2link, a common way to obtain such complexes will include the synthesis of a suitable precursor containing two monogamistic diamine /stage 1/, subsequent treatment with an acid, such as dilute HCl, which gives the corresponding protonated amine RNH3+Cl-that can then be used as source material for further metallation /stage 2/; and the subsequent interaction with two equivalents of the corresponding Pt(b) target to give the desired product /stage 3/:

< / BR>
Synthesized source Pt(a)-predecessor, which contains two monogamistic diamine, will vary depending on the desired group "T" and the desired orientation in the final trehletiem complex, and where T contains at least one anionic or neutral ligands mentioned above. Examples of suitable Pt(a)-precursors include, for example, CIS - or TRANS- [PtCl2(H2N-R-NH3H2N-CH(CH2NH3)2Cl2] , CIS - or TRANS-[PtCl(NH3)(H2N-R-NH3Cl2]2+and (where "small" means malonate, in primary forms or any)of CIS- [Pt(Mal)(H2N-R-NH3Cl)2].

Upon receipt trehmetrovyh complexes of the formula (III) Pt(a), the precursor will have, preferably, a "bent" structure due to triamcinolone bridging agent, which is attached to it. In particular, Pt(a), the precursor will preferably have the General structure

< / BR>
or

< / BR>
For example, a suitable Pt(a) the predecessor is:

< / BR>
Such Pt(a) is a predecessor then subjected to the interaction with two equivalents of a suitable target molecules Pt(b) to obtain the required trehlitrovy complex. Similarly molecule-target Pt(b) with stage 3, which must interact with the protonated amine, obtained in stage 2 will be selected based on the desired radicals X, Z and Y, and their orientation in the final trehletiem complex. Examples of suitable target molecules Pt(b) include, for example, [PtLCl3]-(where L represents NH3, RNH2, R R"SO, py/, CIS - or TRANS-[PtCl2(NH3)2] and CIS - or TRANS-[PtCl2(RNH2)2].

Stage 2. Treatment of platinum-diamino predecessor (I) acid to obtain the protonated diamine (II)

< / BR>
Stage 3. Getting trehmetrovogo complex by interaction of the protonated diamine (II) with the compound-target Pt(b)

< / BR>
For example, here the molecule-target selected K[PtCl3(NH3)], as is the substitution of Cys relatively ligand NH3. However, the precursor molecule and the target will, of course, vary depending on the desired structure trehmetrovogo complex, in particular, the desired X, Y, Z and T and their relative locations in the received result of the TSS, as described above, except that Pt(a) to the monomer precursor or a target molecule Pt(b) used to obtain trehmetrovogo complex will contain platinum in the oxidation state of Pt(IV), or the above-mentioned trehlitrovy complex of formula (I) or (II) is oxidized to obtain the corresponding containing Pt(IV) trehmetrovyh complexes. If trehmetrovyh complexes of the formula (IV), where all three platinum radical have the oxidation state 4+, Pt(II)-trehlitrovy complex of formula (I), (II) or (III) may be oxidized to obtain complex having three units of Pt(IV).

For trehmetrovyh complexes of the formula (V) containing a single unit of Pt(IV), Pt(a)-the predecessor to the degree of oxidation of 2+ will be oxidized to the corresponding Pt(a) the predecessor with the oxidation state 4+. Then, this precursor will be associated with two molecules of target Pt(b), as described above.

Upon receipt trehmetrovyh complexes of the formula (VI), which contain two units of Pt(IV), the molecule-target Pt(b) to oxidize the oxidation state 4+ before binding to Pt(a) the predecessor with the oxidation state 2+.

Trehplastinnaya complexes of the present invention are intended for pharmaceutist increased cytotoxic activity in comparison with currently available platinum complexes. The complexes in question will be used for the treatment of diseases and conditions which are identical to those for which treatment is used cisplatin. This includes the treatment of tumors, radiation sensitization or augmentation /Douple et al., Cisplatin Current Status and Development, Eds. A. W. Prestayk. et al., Academic Press, 125 (1980), Douple et al., Platinum Metals Res. , 1985, 29, 118/, and treatment of parasitic conditions, such as sleeping sickness /Farrel et al., Biochem. Pharmacol., 1984, 33, 961/. The complexes of the present invention will be introduced, mainly, in the same doses as cisplatin, although considering the magnitude LD50specific trehmetrovogo complex. Usually trehlitrovy complex together with a pharmaceutically acceptable carrier. For example, the complex and the carrier can be in the composition for parenteral or oral administration, is well known in the art. Of pharmaceutically acceptable carriers and methods of formulation, see, for example, Remington''s Pharmaceutical Sciences.

Due to their structures trehplastinnaya complexes should be useful in the treatment of cancer, parasitic diseases and other conditions under which currently find therapeutic application of the platinum complexes. therapeutic effectiveness of a particular trehmetrovogo to tinawag complex can be assessed in vitro, based on its cytotoxicity against cancer cells L1210 cancer cells P388 cancer cells or L1210 or P388 resistant to this drug called cisplatin. In particular, testing with L1210 are adopted by way of selection of platinum complexes according to their therapeutic activity.

Those trehplastinnaya complexes which exhibit cytotoxic activity, for example, against L1210 cells will then be tested in vivo in animals, for example on naked mice containing implanted human tumors. Those trehplastinnaya complexes that are active in vivo without significant adverse effects /for example, nephrotoxicity/ will be tested clinically.

To more fully illustrate the present invention and its advantages are the following examples, and it should be understood that these examples are intended for illustration only and is not meant to limit the present invention.

Example 1.

Obtaining CIS-[{CIS-PtCl2(NH3)( -H2N(CH2)4NH2)}2PtCl2].

Getting this connection is shown schematically above. In fact, the experimental methods used by applicants for the synthesis of this complex, trowunna solution 0,8579 g K2PtCl4dissolved in 7 ml of water is added dropwise 0,8371 g H2N(CH2)4NH(Boc)) in 5 ml of water. The mixture is stirred for 5 h, during which landed a solid cream color. The solid is collected in the funnel with a glass filter, washed with water and acetone and dried.

(195Pt) in DMF = -2226 M. D.

Elemental analysis for C16H40N4Cl2O4Pt

Calculated: C 33,65; H 6,27; N 8,72; Cl 10,83.

Found: C 33,90; H To 6.43; N 8,80; Cl 11,23.

Complex II CIS-[PtCl2(H2N(CH2)4NH3)2Cl2]

Suspended 0,4516 g of CIS-[PtCl2(H2N-R-NH(Boc))2] in 10 ml of MeOH and 2 ml of water. To the suspension with stirring, slowly add 10 ml of concentrated HCl. After some time cream solid is dissolved with the formation of a yellow solution. The solution is dried to dryness in a stream of nitrogen and the resulting yellow solid is washed with acetone and dried with a gun for drying above the boiling acetone. Complex II is fully soluble in water, the characteristics of complex II:

Elemental analysis for C8H26N4Cl4Pt

Calculated: C 18,65; H 5,09; N 10,87; Cl 27,52.

Found: C rate 18.89; H of 5.40; N 10 the IIIa with CIS-[{CIS-PtCl2(NH3)( -H2N(CH2)4NH2)}2PtCl2]

Dissolve 0,713 g of CIS-[PtCl2(H2N-R-NH3)2Cl2] in 3 ml of water and add a solution 1,5828 g K[PtCl3(NH3)] in 12 ml of water. Added dropwise with stirring 0.18 g of KOH in 5 ml of water. Within 3 minutes, it begins to form a yellow precipitate. After one hour, filtered off solid IIIa, washed with water and acetone and dried.

Elemental analysis for C8H30N6Cl6Pt3(IIIa)

Calculated: C At 9.53; H 3,00; N 8,33; Cl 21,10.

Found: C 9,34; H 2,90; N 8,02; Cl 20,30.

Complex IIIc CIS-[{CIS-Pt(Mal)(NH3)( - H2N(CH2)4NH2)}2Pt(Mal)]

Malonate receive a standard way by Kraker et al., /J. Med. Chem. (1992), 35, 4526/ by stirring the suspension IIIa in the water with three equivalents of malonate silver within 48 h AgCl precipitated and filtered, the filtrate is evaporated to half volume, and the product precipitated with acetone. Complex white then recrystallized from water and acetone.

Elemental analysis for C17H36N6O12Pt33H2O (IIIc)

Calculated: C 17,67; H 3,66; N 7,27.

Found: C 17,66; H 3,72; N 6,57. MS (FAB)+the original ion: 1102 /calc. 1102/.

3)2]Cl2< / BR>
As mentioned above, the scheme of the synthesis described above for obtaining discussed trehmetrovyh complexes, applicable for a wide range of Pt(a) precursor and molecules of target Pt(b), depending on the desired groups X, Y, Z and T and the desired orientation in the final trehmetrovyh complexes. For example, the interaction of CIS-[PtCl2(NH3)2] c H2N(CH2)4(Boc) gives tetramin.

Stage 1

CIS-[PtCl2(NH3)2] + 2H2N(CH2)4NH(Boc) ---> CIS-[Pt(NH3)2(H2N(CH2)4NHBoc)2]Cl2< / BR>
IV

and

Stage 2

CIS-[Pt(NH3)2(H2N(CH2)4NHBoc)2]Cl2< / BR>
IV

---> CIS-[Pt(NH3)2(H2N(CH2)4NH3)2Cl2]Cl2< / BR>
V

The interaction of V with K[PtCl3(NH3)] gives the cation VIa containing two CIS-[PtCl2(Amin)2]-group related through the link [Pt(amine)4]:

Stage 3

2K[PtCl3NH3] + CIS-[Pt(NH3)2(H2N(CH2)4NH3)2]Cl2< / BR>
V

---> CIS-[{CIS-PtCl2(NH3)( - H2N(CH2)4NH2)}2Pt(NH3)2]2+< / BR>195Pt NMR. The metathesis VIa education VIb can be achieved by processing VIa [Pt(NH3)4Cl2] in the water, which selectively precipitates substantially insoluble salt [Pt(NH3)4][PtCl3(NH3)2] leaving trehlitrovy cation in solution in the form of a chloride salt.

Experimental methods in example 2.

Complex IV CIS-[Pt(NH3)2(H2N(CH2)4NHBoc)2]Cl20.45 g of CIS-DDP suspended in 75 ml of water at 70 - 80oC under stirring. 0.6 g of H2N(CH2)4NHBoc (a slight excess of the stoichiometric 1:2) dissolved in 10 ml of water and added to the suspension. Continue stirring at 70 - 80oC for 4 h, during which forms a colourless solution. After cooling the solution is filtered with activated carbon through celite. Then the filtrate is evaporated to 2 ml, and add 50 ml of acetone. After cooling, 3oC during the night the precipitated white product is filtered and washed with acetone.

Elemental analysis for C16H46N6Cl2O4Pt

Calculated: C 31,95; H 6,85; N 12,42; Cl 10,48.

Found: C 31,75; H 6,90; N 12,12; Cl 10,29.

NMR in D2O: (1H): IS 3.08, 2,7 UB>3)2Cl2]Cl2< / BR>
0.8 g of complex IV are suspended in 10 ml of MeOH and 2 ml of water. To the suspension while mixing, slowly add concentrated HCl (10 ml). After 2 h the solution is filtered and the filtrate evaporated to dryness. Under stirring for 2 h add MeOH (200 ml) and the solution is filtered. The filtrate is evaporated to 10 ml and cooling plant product.

Elemental analysis for C8H32N6Cl4Pt

Calculated: C 17,49; H 5,96; N 15,30; Cl 25,82.

Found: C 17,20; H 5,96; N 15,01; Cl 25,53.

NMR in D2O: (1H): 3,02, 2,75, 1,73 m D., (195Pt): - 2651 M. D.

The complex VIa CIS-[{CIS-PtCl2(NH3)( - H2N(CH2)4NH2)}2Pt(NH3)2] [PtCl3(NH3)]2< / BR>
0.1 g of complex V was dissolved in 2 ml of water and add 0.5 ml of 1M KOH. The solution is added dropwise to a solution of K[PtCl3(NH3)] (0.15 g) in 5 ml of water with stirring for 2 hours the Solution is filtered and added dropwise 30 ml of MeOH, precipitating a light yellow product.

Elemental analysis for C8H42N10Cl10Pt5< / BR>
Calculated: C 5,97; H 2,63; N 8,71; Cl 22,04.

Found: C 6,72; H To 2.57; N 8,71; Cl 20,89.

Complex VIb CIS-[{CIS-PtCl2(NH3)( - H2N(CH2)4NH3)4]Cl2in 1 ml of water. Cooling of the solution to 3oC during the night gives a Golden yellow precipitate of [Pt(NH3)4] [PtCl3(NH3)]2and the supernatant decanted and evaporated to half volume. The supernatant is again decanted additional precipitated salts tetraamine and evaporated it to 5 ml Add 20 ml of MeOH and cooled during the night gives a small amount of product.

Elemental analysis for C8H36N8Cl6Pt3(VIb)

Calculated: C Which 9.22; H 3,48; N 10,75; Cl 20,41.

Found: C 8,99; H 3,61; N 10,28; Cl 20,25.

In table. 1 and 2 shows excerpts from the available pharmacological data IN VITRO.

Although the invention is described with preferred embodiments of the invention skilled in this technical field will be clear that various modifications, substitutions, omissions and changes may be made without deviating from the invention. Accordingly, it is intended that the scope of the present invention is limited only by the amount of the following next of the claims.

1. Trehlitrovy complex of Pt(II) General formula I

< / BR>
where X, Y, Z, and T is neutral and/or anionic ligands, which may be the same the

And includes diamino bridge agent;

n+- full charge trehmetrovyh coordination spheres;

R is one or more counterions, which may be present or not be present depending on whether have or not have three platinum coordination sphere of total charge;

n represents the total charge of the counterions, which is such that the received trehlitrovy complex was neutral;

m = 0-2 is the number of counterions.

2. Trehlitrovy complex p. 1 wherein the neutral ligand is NH3.

3. Trehlitrovy complex p. 1 wherein the anionic ligand is chloride or malonate.

4. Trehlitrovy complex p. 1, where diamino bridge agent represented by the General formula-NH2-(CH2)s-NH2and S = 4.

5. Trehlitrovy complex under item 1, where the counterion P is Cl-.

6. Trehlitrovy complex under item 1, which is CIS-[{ CIS-PtCl2(NH3)( - H2N(CH2)4NH2)}2PtCl2].

7. Trehlitrovy complex under item 1, which is CIS-[{ CIS-Pt(Mal)(NH3)( - H2N(CH2)4NH2)}2Pt(Mal)].

)4NH2)}2Pt(NH3)2]Cl2.

9. The method of obtaining trehmetrovogo complex p. 1, characterized in that includes: (1) obtaining predecessor-the platinum Pt(a) is a monomer containing two monosubstituted djaminovich bridging agent, where one end of each diamino bridge is not included in the complex and contains NH+3- salt, (2) processing the specified predecessor platinum Pt(a) monomer acid to obtain the corresponding protonated amine and (3) interaction specified protonated precursor monomer platinum with two equivalents of module supply target Pt(b).

10. The method according to p. 9, characterized in that the platinum monomer precursor is selected from the group consisting of CIS-[PtCl2(H2N-R-NH3CL)2] , CIS-[Pt(NH3)2(H2N-R-NH3Cl)2]2+where R is an alkyl group.

11. The method according to p. 9, characterized in that the molecule-target Pt(b) represents a General formula [PtLCl3]-where L - NH3.

 

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