Polymer derivative of cytidine antimetabolite

FIELD: medicine.

SUBSTANCE: invention refers to a polymer derivative of cytidine antimetabolite of formula (1) which can be used as an antineoplastic drug: (1), where R is hydrogen or alkyl; A is hydrogen, acyl or alkoxycarbonyl; m is within 3 to 200; n is within 5 to 2000; X is a residue of cytidine antimetabolite, hydroxyl or a hydrophobic substitute, and X means a residue of cytidine antimetabolite in amount 3-100 % m, hydroxyl in amount 0-95 % m and the hydrophobic substitute in amount 0-80 % m.

EFFECT: preparation of new antineoplastic compounds.

8 cl, 5 ex, 4 tbl

 

The technical field to which the invention relates

The present invention relates to a polymer derived antimetabolite of cytidine, the use of a specified substance and the method of its production.

The level of technology

For the treatment of malignant tumors, viral diseases were created different antimetabolites of cytidine; cytarabine, gemcitabine and similar tools are used in clinical settings as antineoplastic (anticancer) funds, and zalcitabine, lamivudine and similar tools are used as antiviral agents.

However, many of these antimetabolites of cytidine are not sufficiently effective or require high doses because of their susceptibility to metabolism and excretion in vivo despite strong activity in vitro. As an example, it can be noted that gemcitabine has a strong activity of inhibiting the growth of cells in vitro in comparison with other anti-cancer agents like paclitaxel and doxorubicin, but requires the introduction in the clinical setting at the highest dose, 1000 mg/m2the surface area of the body. It is believed that this effect is due to the fact that the amino group in position 4 of the base metabolized and inactivated by titidindezaminazoy, enzyme metabolizing 2'-desac icitizen, resulting in reduced bioavailability of this tool in vivo (see non-patent document 1).

The binding of the drug with the polymer sometimes can improve its pharmacokinetics in vivo and to enhance therapeutic effect. In non-patent document 2 describes a polymer derivative, in which cytarabine is associated with polyglutamine acid with an average molecular weight of about 30,000. However, polymer derived medicines sometimes cause an allergic reaction caused by the immune response, and in such a situation can not be re-introduced as a medicine.

In patent document 1 described polymer derivative, which derivative cytidine associated with polyethylene glycol, and non-patent document 3 describes a polymer derivative, in which cytarabine is associated with aspartic acid in polyethylene glycol, with aspartic acid substituted at both ends of the Daisy chain. However, there is also the possibility that therapeutic action of these polymeric derivatives in the clinical environment will be significantly affected by the individual characteristics of the treated subjects, as the release of drug from these derived largely depends on the hydrolysis under ondastan enzyme in vivo.

In patent document 2, it is shown that the molecules in which the drug is associated with blockcopolymers obtained by condensation of ethylene glycol with poliasparaginovaya acid form micelles necessary for obtaining medicines. In addition, in patent document 3 describes a polymer in which an anti-cancer substance associated with the carboxyl groups of the side chain of glutamic acid blockcopolymer obtained by condensation of ethylene glycol with polyglutamine acid. However, in these patent documents, there are no data about the use of antimetabolites of cytidine as related medicines.

Non-patent document 1: Cancer Science, Japanese Cancer Association, Vol.95, p.105-111 (2004).

Non-patent document 2: Cancer Research, American Association for Cancer Research, Vol.44, p.25-30 (1984).

Non-patent document 3: Journal of Controlled Release (Elsevier, England), Vol.79, p.55-70 (2002).

Patent document 1: publication of patent applications Japanese (KOHYO) No. 2003-524028.

Patent document 2: Japan patent No. 2694923.

Patent document 3: publication of the patent application of Japan (KOKAI) No. 05-000955.

Description of the invention

Objectives of the invention

The object of the present invention is an antimetabolite of cytidine with a higher efficiency at low dose and being new anticancer or against the viral tool.

Means to solve the aforementioned problems

As a result of extensive research aimed at solving the above problems, the present invention has created a polymer derived antimetabolite of cytidine, in particular the connection, in which the structure of the amino group in position 4 of the antimetabolite cytidine linked by an amide bond with a carboxyl group of a polymeric compound consisting of polietilenglikoli part and the polymer part containing carboxyl groups in side chains, which formed the basis of the present invention.

In particular, the present invention relates to the following objects(1)-(13).

(1) a Polymer derived antimetabolite of cytidine, in which the structure of the amino antimetabolite of cytidine linked by an amide bond with a carboxyl group in the side chain polymeric compounds consisting of polietilenglikoli part and the polymer part containing carboxyl groups in the side chains.

(2) a Polymer derived antimetabolite of cytidine described in the above item (1), in which the polymer part containing a carboxyl group in the side chain includes a chain polyglutamine acid.

(3) a Polymer derived antimetabolite of cytidine described in the above item (1) or (2), which is a compound expressed by General F. what rmulas (1):

Formula 1

where R means a hydrogen atom or C1-C6 alkyl group; a represents a hydrogen atom, C1-C6 acyl group, or C1-C6 alkoxycarbonyl group; m denotes a number from 3 to 200 as an average value; n denotes a number from 5 to 2000 average value; x is the residue of the antimetabolite of cytidine, pyroxyline group or a hydrophobic Deputy, and X means the rest of the antimetabolite of cytidine in the amount of 3-100% m hydroxyl group in the amount of 0-95% m and hydrophobic substituent in the amount of 0-80% m.

(4) a Polymer derived antimetabolite of cytidine described in the above item (3), in which R is C1-C3 alkyl group; a represents C2-C4 acyl group; and m denotes a number from 5 to 100 as an average value; n represents the number from 50 to 1000 as an average value; and the rest of the antimetabolite of cytidine means a group expressed by the formula (2):

Formula 2

where Z means a hydrogen atom or a fluorine atom; -Rf stands for a group selected from groups containing substituents of the formula (3):

Formula 3

(5) a Polymer derived antimetabolite of cytidine described in the above item (3), in which R denotes a methyl group; a represents acetyl group; and m denotes a number from 10 to 60 in the form of secondary importance is to be placed; n denotes a number from 100 to 300 as an average value; x is the residue of the antimetabolite of cytidine or hydroxyl group; and an antimetabolite of cytidine means cytarabine, gemcitabine or 5'-deoxy-5-perltidy.

(6) a Polymer derived antimetabolite of cytidine described in the above item (3) or (4), in which hydrophobic Deputy means derived α-amino acids expressed by the formula (4):

Formula 4

where Q denotes a side chain of a neutral amino acid; W stands for C1-C6 alkyl group or benzyl group.

(7) a Polymer derived antimetabolite of cytidine described in the above item (6)in which Q means ISO-propyl group or a benzyl group, and W means a benzyl group.

(8) a Polymer derived antimetabolite of cytidine described in the above item (3) or (4), in which hydrophobic Deputy means a group expressed by the formula (5):

Formula 5

O-T (5)

where T denotes C1-C6 alkyl group optionally substituted phenyl group.

(9) a Polymer derived antimetabolite of cytidine described in the above item (8)where T denotes benzyl group, 3-phenylpropyl group, 4-phenylbutyl group or 5-phenylmethylene group.

(10) a Polymer derived antimetabolite cited is on, described in the above item (3), in which R denotes a methyl group; a represents acetyl group; and m denotes a number from 10 to 60 as an average value; n represents the number from 100 to 300 as an average value; an antimetabolite of cytidine means cytarabine, gemcitabine or 5'-deoxy-5-perltidy; and hydrophobic Deputy means benzyloxy, 4-fenilbutazonu group, (1-benzyloxycarbonyl-2-methyl)propylamino or (1-benzyl-oxycarbonyl-2-phenyl)ethylamino.

(11) an Antitumor agent containing polymer derived antimetabolite of citydata described in any of the above items (1)to(10), as a medicinal component.

(12) an Antiviral agent containing polymer derived antimetabolite of cytidine described in any of the above items (1)to(10), as a medicinal component.

(13) a method of obtaining a polymer derived antimetabolite of cytidine described in any of the above items (1)to(10), which includes linking amide bond, using the agent for dehydrocondensation in an organic solvent, the amino group of the antimetabolite cytidine with a carboxyl group in the side chain polymeric compounds consisting of polietilenglikoli part and the polymer part containing a carboxyl group in the side CE is s.

The effect of the invention

Polymer derived antimetabolite of cytidine of the present invention has a structure in which the amino group in position 4 of the antimetabolite cytidine linked by an amide bond with a carboxyl group of a polymeric compound consisting of polietilenglikoli part and the polymer part containing carboxyl groups in the side chains. Specified derivative can slowly release the antimetabolite of cytidine in vivo and are suitable for use as anticancer or antiviral agents, providing excellent therapeutic effect at a lower dose. In addition, due to the slow release of drugs, regardless of the enzyme on therapeutic effect of said derivative to a lesser extent influenced by the individual characteristics of the treated subjects. Polymer derivative, forming micelles, selectively accumulate in the affected part of the body and is characterized by higher efficiency with less pronounced side effects.

Brief description of drawings

Figure 1 shows a graph showing the time of the release of the medicinal product in the absence of the enzyme.

Figure 2 is a graph showing the time of the release of the drug in plasma mouse.

The best option implemented is tvline inventions

Polymer derived antimetabolite of cytidine under this Sarateni has a structure in which the amino group of the antimetabolite cytidine linked by an amide bond with a carboxyl group in the side chain polymeric compounds consisting of polietilenglikoli part and the polymer part containing carboxyl groups in the side chains.

In accordance with the purposes of the present invention, the term “antimetabolite of cytidine” has no particular restrictions, provided that an antimetabolite of cytidine is derived 4-aminopyrimidine-2-she has antitumor or antiviral activity and is a compound expressed by formula (2), in which part of the Foundation of the nucleic acid is a cytosine (where Z means a hydrogen atom) or 5-fertilizing (where Z means a fluorine atom); and the associated group (Rf) is a group selected from the group that includes the substituents of the above formula (3).

Specific examples of antimetabolite of cytidine include cytarabine, gemcitabine, 2'-deoxy-2'-matricectomy (DMDC), tezacitabine, zalcitabine, lamivudine, 5'-deoxy-5-perltidy (5'-DFCR), troxacitabine, 2'-C-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (CNDAC), 3'-ethnicities and (-)-β-L-deoxyactein.

In accordance with the present invention, examples of the polymer part containing carbon the ilen groups in side chains, the term “polymeric compound consisting of polietilenglikoli part and the polymer part containing carboxyl groups in the side chains are grafted copolymer, in which chain carboxylic acids were branched from the main chain of the polymer, or block copolymers, in which the condensed polymers of polycarboxylic acid.

Examples of the polymer compound in which the polymer part containing a carboxyl group in the side chain is grafted copolymer include a polymer obtained, for example, by copolymerization of a condensate of polyethylene glycol and acrylic acid with acrylic acid, maleic anhydride or the like, followed by optional hydrolysis, in accordance with the description given in the publication of the patent application of Japan (KOKAI) No. 11-279083.

Examples of the polymer compound in which the polymer part containing carboxyl groups in the side chains, is blockcopolymers include the link in which the polyethylene glycol having a terminal functional group is associated with a polycarboxylic acid having a terminal functional group, or a compound obtained by polymerization of compounds of the activated amino acid, in which polymerization begins with a polyethylene glycol having a terminal amino group, in accordance with the tvii description, described in patent document 3.

Examples of the polymer containing carboxyl groups in side chains, include polyacrylic acid, polymethacrylic acid, polymer malic acid and polyglutamic acid; the preferred acid is polyglutamine acid.

In accordance with the purposes of the present invention the polyethylene glycol may be a derivative of polyethylene glycol, which modified both or one end, in this group, modifying both ends, may be the same or different. Examples of terminal modifying groups include C1-C6 alkyl group, optionally having a Deputy; the preferred group is a C1-C4 alkyl group optionally having a substituent.

Examples of C1-C6 alkyl group in C1-C6 alkyl group, optionally having a Deputy, include C1-C6 alkyl group with a straight or branched chain or cyclic structure. Specific examples of such groups include methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, tert-boutelou group, pentelow group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexoloy group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl g is the SCP, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethyl-boutelou group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group, cyclopropyl group, cyclopentyl group and tsiklogeksilnogo group. The preferred group is a C1-C4 alkyl group, specific examples of which include methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, sec-boutelou group and tert-boutelou group. Especially preferred group is a methyl group, ethyl group, n-sawn group or isopropyl group.

Deputy in C1-C6 alkyl group, optionally having a Deputy, has no particular limitation, and examples include amino group, methylaminopropyl, dimethylaminopropyl, ethylamino and diethylaminopropyl. The preferred group is the amino group.

In accordance with the present invention, it is preferable derivative of polyethylene glycol, which modified both ends. Specific examples of the derivative include a derivative of polyethylene glycol containing C1-C6 alkyl group at one end and an amino-C1-C6 alkyl group at the other end. The preferred derivative is derived polyethylene is glycol, containing C1-C3 alkyl group at one end and an amino-C1-C4 alkyl group at the other end. Especially preferred is a derivative of polyethylene glycol containing a methyl group at one end and aminopropyl group at the other end.

In accordance with the present invention the polyethylene glycol has an average molecular weight equal to about 200-500000, preferably about 500-100000, more preferably about 2000-50000.

In accordance with the present invention a polymeric compound consisting of polietilenglikoli part and the polymer part containing a carboxyl group in the side chain, preferably is blockcopolymers, more preferably by blockcopolymers of polyethylene glycol and a polymer containing carboxyl groups in the side chains.

Examples of blockcopolymer of polyethylene glycol and a polymer containing carboxyl groups in side chains, include block copolymers of alkoxyalkanols and polyacrylic acids, block copolymers of alkoxyglycerols and poly (methacrylic acid) and block copolymers of alkoxyalkanols and polyglutamine acid; the preferred blockcopolymer is a block copolymers of methoxypolyethyleneglycol and polyglutamine acid.

In accordance with the present invention a polymeric compound consisting the e of polietilenglikoli portion and a polymeric portion, containing carboxyl groups in the side chains, on average, contains in one molecule is from about 3 to 200 carboxyl groups, preferably from about 5 to 100, more preferably from about 10 to 60.

In accordance with the present invention a polymeric compound consisting of polietilenglikoli part and the polymer part containing a carboxyl group in the side chain has an average molecular weight equal to about 500-500000 preferably about 2000-100000, more preferably about 3000-50000.

In accordance with the present invention, the number of antimetabolite of cytidine associated amide bond with a polymer compound consisting of polietilenglikoli part and the polymer part containing carboxyl groups in side chains, has no particular restrictions, provided that the specified number is in the range from one to the total number of carboxyl groups in each polymer compound is sufficient to provide a drug action when introduced in vivo. The preferred quantity is 3-100%, more preferably 5-70% of the total number of carboxyl groups of the polymer.

The above link number can be determined on the basis of the intensity of the ultraviolet absorption spectrum of the compounds according to the present invention. The specified amount is in can also determine exposing a polymer derived antimetabolite of cytidine of the present invention the alkaline gidrolizu for the quantitative determination of free antimetabolite of cytidine, for example, by high-performance liquid chromatography.

Typical polymeric derivative of the antimetabolite cytidine of the present invention is a compound expressed by the above General formula (1), in which R means a hydrogen atom or C1-C6 alkyl group; a represents a hydrogen atom, C1-C6 acyl group, or C1-C6 alkoxycarbonyl group; m denotes a number from 3 to 200 as an average value; n denotes a number from 5 to 2000 average value; x is the residue of the antimetabolite of cytidine, a hydroxyl group or a hydrophobic Deputy, and X means the rest of the antimetabolite of cytidine in the amount of 3-100% m, a hydroxyl group the number of 0-95% m and hydrophobic substituent in the amount of 0-80% m.

In the formula (1) C1-C6 alkyl group for R has the same meaning as the above alkyl group; preferred group also has the above value.

Examples of C1-C6 acyl group for a in the formula (1) include formyl group, acetyl group, propionyl group, butyryloxy group, isobutyryloxy group, valerino group, isovaleryl group, pivaloyl group and hexane is safe group. The preferred group is a C2-C4 acyl group, for example acetyl or propylaniline group; more preferred group is the acetyl group.

Examples of C1-C6 alkoxycarbonyl group a in the formula (1) include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, tert-butoxycarbonyl group, phenoxycarbonyl group, hexyloxymethyl group, cyclopropanecarbonyl group, cyclopentanecarbonyl group and cyclohexyloxycarbonyl group. The preferred group is methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group or tert-butoxycarbonyl group; more preferred group is ethoxycarbonyl group or tert-butoxycarbonyl group.

In the formula (1) m means in the form of the average value of the number equal 3-200, preferably 5-100, more preferably 10-60.

In the formula (1) n means the average value of the number equal to 5-2000, preferably 50-1000, more preferably 100-300.

In the General formula (1) polymer derived antimetabolite of cytidine of the present invention derivatives of glutamic acid, in which X OSN which includes the remainder of the antimetabolite cytidine, hydroxyl group or a hydrophobic Deputy can be connected arbitrarily, or by formation of blocks.

In the formula (1) the rest of the antimetabolite of cytidine for X means the residue of the above antimetabolite of cytidine; particularly preferred examples of antimetabolite of cytidine include cytarabine, gemcitabine and 5'-deoxy-5-perltidy.

In the formula (1) examples of the hydrophobic substituent for X include different substituents; specified the Deputy has no particular restrictions, provided that it does not reduce therapeutic effect of polymer derived antimetabolite of cytidine. However, preferred examples of the mentioned substituent include a derivative of α-amino acids expressed by the above formula (4), where Q denotes a side chain of a neutral amino acid; W stands for C1-C6 alkyl group or benzyl group, and a group expressed by the above formula (5), where T denotes C1-C6 alkyl group optionally substituted phenyl group.

Examples of side-chain neutral amino acids for Q in the formula (4) include residues of natural amino acids, such as hydrogen atom, methyl group, isopropyl group, isobutylene group, sec-bucilina group, benzyl group, hydroxymethylene group, 1-hydroxyethylene group, carbamoylmethyl group and 2-carbamoylethyl group is a, and derivatives of amino acid residues, such as tert-butoxymethyl group, benzoyloxymethyl group, benzyloxycarbonylamino group and 2-benzyloxycarbonylamino group. Preferred examples of these groups include ISO-propyl group, isobutylene group, sec-boutelou group, benzyl group, benzoyloxymethyl group, benzyloxycarbonylamino group and 2-benzyloxycarbonylamino group; more preferred group is ISO-propyl group, benzyl group, benzyloxyethyl group or 2-benzyloxycarbonylamino group; especially preferred group is ISO-propyl group or a benzyl group.

Examples of C1-C6 alkyl group for W in the formula (4) include the same groups as the above-mentioned alkyl group; preferred group similar to the above group.

C1-C6 alkyl group for T in the formula (5) has the same meaning as the above alkyl group; preferred group is also similar to the above group. Examples of the group expressed by the formula (5)include metaxylene group, ethoxyline group, n-propoxyphenyl group, isopropoxyphenyl group, n-butoxyl group, tert-butoxyl group, n-pentyloxy, n-hexyloxy, cyclopropylamino, cyclopentyloxy, cyclohexyloxy the PU, cyclohexylmethoxy group, benzyloxy, 2-penetrometry, 3-phenylpropoxy group, 4-fenilbutazonu group, 5-finalinternship and diphenylmethylene group.

Examples of the hydrophobic substituent include an amino group, such as methylaminopropyl, atramentaria, n-propylamino, isopropylamino, n-butylamino, isobutylamino, n-pentylamine, n-hexylamine, cyclopropylamino, cyclopentylamine, cyclohexylamine, cyclohexylethylamine, dicyclohexylamine, aniline group, benzylamino, 2-phenethylamine, 3-phenylpropylamine, 4-phenylbutyramide and diphenylethylamine.

Hydrophobic Deputy for X in the formula (1) is particularly preferably is benzyloxycarbonyl, 3-phenylpropoxy group, 4-phenylbutazone group, 5-phenylphenoxide group, (1-benzyloxycarbonyl-2-methyl)propylamino or (1-benzyloxycarbonyl-2-phenyl)arylaminopoly and more preferably is benzyloxycarbonyl, 4-phenylbutazone group, (1-benzyloxycarbonyl-2-methyl)propylamino or (1-benzyloxycarbonyl-2-phenyl)arylaminopoly.

In the formula (1) fraction of residue of the antimetabolite cytidine for X is 3-100%, predpochtitelno 5-70% in terms of total number of carboxyl the s group (m) of the polymer; the proportion of hydroxyl group for X is 0 to 95%, preferably 5-70% in terms of m; and the share girotondo Deputy for X is 0-80%, preferably 20-70% in terms of m.

In polymer derived antimetabolite of cytidine of the present invention in the presence of carboxyl group in the side chain, which is not connected an antimetabolite of cytidine specified carboxyl group may be in free form or in salt form alkali metal. The carboxyl group is obtained in a free form can be converted into a desired salt by a method known in this field, or method. Conversely, the carboxyl group is obtained in salt form, can be converted into a free form or another desired salt by a method known in this field, or method.

Examples of the alkali metal salt include lithium salts, sodium, potassium, magnesium, ammonium and triethylamine.

In polymer derived antimetabolite of cytidine of the present invention, the structural units forming the polymer part containing carboxyl groups in side chains, can be in the presence of optical isomers of optically active substances, racemate or mixtures thereof in any proportion. For example, when the polymer part containing a carboxyl group in the side chain is derived from a floor is glutamic acid, specified derivative may be a polymer in which poly-L-glutamic acid, poly-D-glutamic acid and L-glutamic acid, substituted in the side chain, or D-glutamic acid, substituted in the side chain, related in any order and in any proportion.

Particularly preferred examples of the polymer derived antimetabolite of cytidine of the present invention include compounds shown in the following table 1.

In table 1 Bzl means a benzyl group; Val means valine; Phe means phenylalanine and C4H8Ph means 4-phenylbutyl group. In the graph X percentage of substitution are approximate values; the remaining residues and groups with the exception of residues and groups listed in the table are hydroxyl groups. As antimetabolites of cytidine for X used the following compounds: cytarabine, gemcitabine, 5'-deoxy-5-perltidy, 2'-deoxy-2'-matricectomy (DMDC), 3'-ethinicities, 2'-C-cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (CNDAC) and (-)-β-L-deoxyactein.

Formula 6

td align="left"> 272
Table 1
No. Rn
(average)
m
(average)
AndX: an antimetabolite of cytidine (percentage)X: the hydrophobic substituent (a percentage value)
1CH327232CH3COCytarabine (30%)OBzl
(50%)
2CH327232CH3COCytarabine (30%)Phe-OBzl (40%)
3CH327225CH3COCytarabine (20%)Phe-OBzl (60%)
4CH327223CH3COGemcitabine (15%)Phe-OBzl (60%)
5CH372 23CH3COGemcitabine (15%)Val-OBzl (60%)
6CH327223CH3COGemcitabine (15%)OC4H8Ph (60%)
7CH327226CH3COGemcitabine (30%)OBzl
(50%)
8CH327226CH3COGemcitabine (30%)Phe-OBzl (40%)
9CH327226CH3COGemcitabine (25%)Phe-OBzl (50%)
10CH327226CH3COGemcitabine (15%)11CH327226CH3COGemcitabine (15%)Val-OBzl (60%)
12CH327226CH3COGemcitabine (25%)OC4H8Ph (40%)
13CH327226CH3COGemcitabine (20%)OC4H8Ph (50%)
14CH327226CH3COGemcitabine (15%)OC4H8Ph (60%)
15CH327232CH3COGemcitabine (30%)Phe-OBzl (40%)
16CH3272 32CH3COGemcitabine (30%)Phe-OBzl (50%)
17CH327232CH3COGemcitabine (20%)Phe-OBzl (60%)
18CH327232CH3COGemcitabine (15%)Val-OBzl (60%)
19CH327232CH3COGemcitabine (15%)OC4H8Ph (60%)
20CH327235CH3COGemcitabine (15%)OC4H8Ph (55%)
21CH327226CH3CO5'-Deoxy-5-perltidy (15%)Phe-OBzl (60%)
22CH327226CH3CO5'-Deoxy-5-perltidy (15%)OC4H8Ph (60%)
23CH327226CH3CO2'-Deoxy-2'-matricectomy (15%)Phe-OBzl (60%)
24CH327226CH3CO2'-Deoxy-2'-matricectomy (15%)OC4H8Ph (60%)
25CH327226CH3CO3'-Ethnicities (15%)Phe-OBzl (60%)
26CH327226CH3CO3'-Ethnicities (15%)OC4H8Ph (60%)
27CH326CH3CO2'-C-Cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (15%)Phe-OBzl (60%)
28CH327226CH3CO2'-C-Cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine (15%)OC4H8Ph (60%)
29CH327226CH3CO(-)-β-L-Dioxopyrimidine (15%)Phwe-OBzl (60%)
30CH327226CH3CO(-)-β-L-Dioxopyrimidine (15%)OC4H8Ph (60%)

As a specific non-limiting example, it may be noted that polymer derived antimetabolite of cytidine of the present invention can be obtained by condensation, using the agent for dehydrocondensation in an organic solvent, antimetabolite of cytidine with blockcopolymers methoxypolyethyleneglycol and polyglutamine the howling acid, obtained by the method described in patent document 3.

The solvent used for carrying out the above reaction, has no particular restrictions, provided that it makes possible the implementation of the reaction; however, the examples of the mentioned solvent include aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, simple ether, such as tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol, nitrile, such as acetonitrile and propionitrile, amide, such as dimethylformamide, dimethylacetamide and N-organic, urea such as 1,3-dimethylimidazolidine, and mixtures of these solvents. The preferred solvent is an amide or urea; the preferred solvent is dimethylformamide or 1,3-dimethylimidazolidine.

Agent for dehydrocondensation used in the above reaction, has no particular restrictions, provided that it makes it possible to carry out the condensation reaction of the amino group in position 4 of the antimetabolite cytidine with a carboxyl group; however, preferred examples of the specified agent include DMT-MM (chloride of 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine) and 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline.

The temperature above which eacli usually equal 4-60°C, preferably 15-50°C.

After performing the above reaction can be performed separation of the products by methods known in this field, such as, for example, concentration in vacuo, extraction with solvent, crystallization, dialysis and chromatography, if desired isolate and purify the desired connection.

Using the above method, you can get polymer derivative in which x is the only remnant of the antimetabolite cytidine or the rest of the antimetabolite of cytidine and hydroxyl group.

When polymer derived antimetabolite of cytidine of the present invention has a hydrophobic Deputy specified derivative can be obtained by condensation, using the agent for dehydrocondensation in an organic solvent, the amino group of the antimetabolite cytidine with the unsubstituted carboxyl group in the side chain polymeric compounds consisting of the following polietilenglikoli part and the polymer part containing carboxyl groups in side chains, which is obtained by introducing a hydrophobic substituent in a part of carboxyl groups of blockcopolymer methoxypolyethyleneglycol and polyglutamine acid, for example, by the method described in patent document 3.

Hydrophobic Deputy impose the following way. For example, when hydro is one Deputy is CNS group the introduction is carried out by condensation of the corresponding alcohol with a carboxyl group (etherification) using the agent for dehydrocondensation in solvent or performing the reaction of nucleophilic substitution of the corresponding alkylhalogenide or similar substances and carboxyl group in the presence of a base in a solvent. For example, when a hydrophobic Deputy is a substituted amino group, a derivative having a Deputy, can be obtained by condensation of the corresponding amine with a carboxyl group (amidation) using the agent for dehydrocondensation in the solvent.

The solvent used in the above dehydrocondensation (etherification), has no particular restrictions, provided that it makes possible the implementation of the reaction. However, this solvent may be the same solvent used for the execution of dehydrocondensation above blockcopolymer methoxypolyethyleneglycol and polyglutamine acid antimetabolite of cytidine; the preferred solvent is also similar to the above-mentioned solvent. Agent for dehydrocondensation has no particular restrictions, provided that it makes possible the implementation of dehydrocondensation alcohol with a carboxyl group; however, the preferred agent is dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-dimethylaminopropyl-3-ethylcarbodiimide, carbonyldiimidazole, isobutylparaben or chloride pavlinovoi acid.

When performing the reaction of dehydrocondensation can be used excipient; examples of such substances include N-hydroxysuccinimide, 1-hydroxybenzotriazole, 4-dimethylaminopyridine and 2,6-di-tert-butyl-4-methylpyridin.

The reaction temperature of dehydrocondensation usually equal 4-60°C, preferably 15-50°C. the reaction Time ranges from 2 hours to several days, preferably 4-48 hours.

The solvent used in the above reactions of nucleophilic substitution, has no particular restrictions, provided that it makes possible the implementation of the reaction. However, this solvent may be the same solvent used for the execution of dehydrocondensation above blockcopolymer methoxypolyethyleneglycol and polyglutamine acid antimetabolite of cytidine; the preferred solvent is also similar to the above-mentioned solvent. Examples of the base include carbonates of alkali metal such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydride such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxide such as lithium hydroxide, sodium hydroxide and the hydroxide is Aliya; the alkali metal alkoxide such as lithium methoxide, sodium methoxide, ethoxide sodium tert-piperonyl potassium; and organic amine, such as triethylamine, tributylamine, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]Nona-5-ene, 1,4-diaza-bicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU); the preferred amine is an organic amine.

The temperature of the above reaction of nucleophilic substitution is usually equal 4-60°C and preferably is in the range from room temperature to 50°C. the reaction Time is from one hour to several days, preferably 4-48 hours.

The solvent used in the above reaction dehydrocondensation (amidation reaction), with no specific limitation provided that it makes possible the implementation of the reaction. However, this solvent may be the same solvent used for the execution of dehydrocondensation above blockcopolymer methoxypolyethyleneglycol and polyglutamine acid antimetabolite of cytidine; the preferred solvent is also similar to the above-mentioned solvent. Agent for dehydrocondensation has no particular restrictions, provided that it makes possible the implementation of dehydrocondensation amines a carboxyl group; however, the preferred agent is dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-dimethylaminopropyl-3-ethylcarbodiimide, carbonyldiimidazole, isobutylparaben, chloride pavlinovoi acid, DMT-MM (chloride of 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine), TFFH (hexaphosphate tetramethylpiperidine) or THIEF (hexaphosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium).

When performing the reaction of dehydrocondensation can be used excipient; examples of excipients include N-hydroxysuccinimide, 1-hydroxybenzotriazole, 4-dimethylaminopyridine and 2,6-di-tert-butyl-4-methylpyridin.

The reaction temperature of dehydrocondensation usually equal 4-60°C and preferably is in the range from room temperature to 50°C. the reaction Time is from one hour to several days, preferably 4-48 hours.

Since the sequence of reactions of binding hydrophobic substituent and the antimetabolite cytidine polymer compound does not matter, these substances can be mixed for the interactions. However, hydrophobic Deputy preferably introduced into the polymer carrier to associate with him antimetabolite of cytidine avoid interaction and decomposition of antimetabolite as the object of activity, containing many of funkcionalnuyu group.

Polymer derived antimetabolite of cytidine of the present invention can form micelles in water with the shell of polietilenglikoli part. The formation of micelles can be identified, for example, by gel-chromatography (GPC) or dynamic light scattering.

In accordance with the present invention the formation of micelles is facilitated through the linking of the carboxyl group, which is not associated with the antimetabolite cytidine, with hydrophobic Deputy.

In the scope of the present invention is an antitumor or antiviral agent containing the above polymer derived antimetabolite of cytidine as a medicinal component. Polymer derived antimetabolite of cytidine can be entered in the form as it is or in the form of pharmaceutical compositions, in which an antimetabolite of cytidine mixed with pharmaceutically acceptable substances. Dosage form pharmaceutical composition may be any dosage form, such as injectable solution, powder, granules, tablets and suppositories. These preparations may also contain various excipients for pharmaceutical applications, that is, the carrier and other excipients, including additives such as a stabilizer, a preservative, a sedative and is alligator.

The content of the polymer derived antimetabolite of cytidine in the product may be different depending on the drug; however, the specified amount is usually 0.1 to 100 wt.%, preferably 1-98 wt.%.

The indication for the use of antineoplastic agents of the present invention containing polymer derived antimetabolite of cytidine as a medicinal component, has no particular restriction; however, this tool can be used to treat different types of cancer, such as, for example, non-small cell lung cancer, pancreatic cancer, stomach cancer, cancer of the colon, colorectal cancer, breast cancer, ovarian cancer, bladder cancer, and AIDS-associated Kaposi's sarcoma.

Indications for use of antiviral agents of the present invention containing polymer derived antimetabolite of cytidine as a medicinal component, has no particular restriction; however, this tool can be used, for example, for the treatment of acquired immunodeficiency syndrome (AIDS), herpes zoster, infectious diseases, caused by herpes simplex virus, and the like, and also to prevent infections.

Polymer derived antimetabolite of cytidine of the present invention can be entered by anyone with the special including oral administration, injection, rectal administration, intraportal introduction, introduction to the composition of the perfusion solution and local injection into the affected organ. However, the preferred method of administration is parenteral administration; the preferred method is intravenous or intra-arterial injection in the form of injection or local injection into the affected organ. Dose polymer derived antimetabolite of cytidine of the present invention may be different depending on the severity of the disease, the route of administration, state of health, age, body mass of the subject and similar factors; however, an acceptable dose is usually 1 mg to 5000 mg, preferably from 10 mg to 2000 mg/m2the surface area of the body, and can be entered once a day or separate portions several times a day. The introduction can be made to repeat daily or at intervals of several days to several months. If necessary, you can use the route of administration, dosing scheme and the introduction of other than above.

Polymer derivative of the present invention also includes a substance in which is connected a prodrug. A prodrug is a chemical derived biologically active parent compound that with the introduction of releases original connection in viv.

Examples

The present invention is described in more detail below with reference to examples, reference examples and test examples. However, the scope of the present invention is not limited to these examples.

Reference example 1. Synthesis of N-acetylated blockcopolymer monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization of approximately 26

The glycol containing metaxylene group at one end and 3-aminopropyl group at the other end (SUNBRIGHT MEPA-12T NOF Corporation, average molecular weight of 12000, 16 g)was dissolved in dimethyl sulfoxide (320 ml), was added to the anhydride of N-carboxylic acid γ-benzyl-L-glutamate (BLG-NCA, 9,48 g; 27 equivalents in terms of polyethylene glycol) and stirred at 30°C during the night. The reaction solution under stirring was added dropwise to a mixed solvent consisting of isopropyl ether and ethanol (4:1, 6.4 l)and stirred for further 3 hours. The precipitate was collected by filtration and washed with a mixed solvent consisting of isopropyl ether and ethanol (4:1, 400 ml). The resulting product (22,78 g) was dissolved in N,N-dimethylformamide (370 ml)was added acetic anhydride (6,83 ml) and stirred at 20°C during the night. The resulting solution under stirring dropwise doba is ranged in a mixed solvent, consisting of isopropyl ether and ethyl acetate (4:1, 3,7 l), and stirred for further 3 hours. The precipitate was collected by filtration and washed with a mixed solvent consisting of isopropyl ether and ethyl acetate (4:1, 300 ml). The resulting product (22,92 g) was dissolved in N,N-dimethylformamide (370 ml)was added 5% palladium on coal (containing 55% water, 2.50 g) and stirred at 30°C in an atmosphere of hydrogen for 4 hours and then at room temperature overnight. Palladium on coal was filtered, the filtrate under stirring was added dropwise to a mixed solvent consisting of isopropyl ether and ethyl acetate (4:1, 5 l), and stirred for another one hour. The precipitate was collected by filtration and washed with a mixed solvent consisting of isopropyl ether and ethyl acetate (4:1, 300 ml). The resulting product (16 g) was dissolved in distilled water (800 ml)was added 1 M aqueous sodium hydroxide solution and brought the pH of the solution to 11. Added distilled water to achieve a final volume of solution equal to 1600 ml, after which was added sodium chloride (80 g). The resulting solution was passed through a column of absorbent resin HP-20ss (Mitsubishi Chemical Corporation Corporation, 500 ml); the column is washed with 5% aqueous solution of sodium chloride (2000 ml) and distilled water (20000 ml) and was suirable 50% aqueous rest the rum acetonitrile (2500 ml). Elyuirovaniya the fraction containing the desired compound was passed through a column of cation exchange resin Dowex 50W (Dow Chemical Company, proton-type, 10 ml); the column was suirable 50% aqueous solution of acetonitrile (150 ml). Elyuirovaniya the fraction containing the desired compound were concentrated under reduced pressure until the volume of the solution 300 ml) and was dried by freezing, while receiving specified in the header connection (15,84 g).

The average polymerization glutamic acid (the number of carboxylic acids) in a single molecule compounds was equal 26,22 on the basis of the indicator titration obtained using an aqueous solution of sodium hydroxide.

Reference example 2. Synthesis of N-acetylated blockcopolymer monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization of approximately 41

In accordance with the method described in reference example 1, to obtain specified in the connection header was used 45 equivalents of BLG-NCA in terms of polyethylene glycol.

The average polymerization glutamic acid (the number of carboxylic acids) in a single molecule compounds was equal to is 41.45 on the basis of the indicator titration obtained using an aqueous solution of sodium hydroxide.

Reference example 3. Synthesis of N-acetylated blockcopolymer monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization of approximately 24

In accordance with the method described in reference example 1, to obtain specified in the connection header has been used 25 equivalents of BLG-NCA in terms of polyethylene glycol.

The average polymerization glutamic acid (the number of carboxylic acids) in a single molecule compounds was equal 23,70 on the basis of the indicator titration obtained using an aqueous solution of sodium hydroxide.

Reference example 4. Synthesis of N-acetylated blockcopolymer monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization of approximately 32

In accordance with the method described in reference example 1, to obtain specified in the connection header has been used 35 equivalents of BLG-NCA in terms of polyethylene glycol.

The average polymerization glutamic acid (the number of carboxylic acids) in a single molecule compounds was equal 31,71 on the basis of the indicator titration obtained using an aqueous solution of sodium hydroxide.

Reference example 5. Synthesis of N-acetylon the bath blockcopolymer monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization, approximately 36

In accordance with the method described in reference example 1, to obtain specified in the connection header was used 40 equivalents of BLG-NCA in terms of polyethylene glycol.

The average polymerization glutamic acid (the number of carboxylic acids) in a single molecule compounds was equal 35,90 on the basis of the indicator titration obtained using an aqueous solution of sodium hydroxide.

Reference example 6. Synthesis of N-acetylated blockcopolymer monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization of approximately 21

In accordance with the method described in reference example 1, to obtain specified in the connection header has been used 23 equivalent of BLG-NCA in terms of polyethylene glycol.

The average polymerization glutamic acid (the number of carboxylic acids) in a single molecule compounds was equal 21,38 on the basis of the indicator titration obtained using an aqueous solution of sodium hydroxide.

Reference example 7. Synthesis of N-acetylated blockcopolymer monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization of approximately 26

In accordance with sosososo, described in reference example 1, to obtain specified in the connection header was used 30 equivalents of BLG-NCA in terms of polyethylene glycol.

The average polymerization glutamic acid (the number of carboxylic acids) in a single molecule compounds was equal 26,48 on the basis of the indicator titration obtained using an aqueous solution of sodium hydroxide.

Reference example 8. Synthesis of amide conjugate complex benzyl ester of L-phenylalanine with N-acetylated by blockcopolymers monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization of approximately 24

The N-acetylated block copolymers monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization of approximately 24 (1,533 g)described in reference example 3 was dissolved in N,N-dimethylformamide (32 ml)was added 4-toluensulfonate complex benzyl ester of L-phenylalanine (0,464 g), TFFH (0,286 g), N,N-diisopropylethylamine (0,672 ml) and 2,6-di-tert-butyl-4-methylpyridine (0,495 g) and stirred the mixture at 37°C for 20 hours. The reaction solution was cooled to room temperature, diluted with ethanol (64 ml) and with stirring was added dropwise diisopropyl ether (256 ml). The mixture was stirred for 30 min is t, the precipitate was collected by filtration and washed with a mixed solvent consisting of diisopropyl ether and ethanol (4:1). The obtained product was dissolved in 30% aqueous solution of acetonitrile (45 ml), deliberately distilled water (2 l × 3) through the dialysis membrane (cut-off molecular weight of from 12000 to 14000). To validirovannoe solution was added acetonitrile (15 ml), the mixture was passed through cation exchange resin Dowex 50W (proton type) and suirable 50% aqueous solution of acetonitrile. Elyuirovaniya the fraction containing the desired compound were concentrated under reduced pressure to 1/2 volume and dried by freezing, while receiving specified in the header connection (1,689 g).

The compound obtained hydrolyzed and produced quantitative determination of released benzyl alcohol using high-performance liquid chromatography (HPLC) to measure the extent of binding of the amide bond group Phe-OBzl in the connection. As a result of measuring the degree of binding was determined as equal to 32.8% in terms of carboxyl group polyglutamine acid.

The method of hydrolysis

Specified in the header connection (34,48 mg) was dissolved in methanol (1 ml)was added 0.5 M aqueous solution of sodium hydroxide (1 ml) and stirred at 40°C for one hour. The neutral solution is savali acetic acid and diluted with distilled water, getting exactly 5 ml of the solution.

Conditions of the analysis by HPLC analysis (benzyl alcohol):

column: Inertsil ODS-3 (particle size: 5 μm), diameter 4.6 x 150 mm;

the column temperature: 40°C;

eluent: solution a: 1% aqueous solution of phosphoric acid, solution b: acetonitrile;

gradient: % solution In (time: minutes) 30 (0), 80 (10);

flow rate: 1 ml/min;

detector (wavelength detection): UV (260 nm).

Reference example 9. Synthesis of amide conjugate complex benzyl ester of L-phenylalanine with N-acetylated by blockcopolymers monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization of approximately 41

The N-acetylated block copolymers monometoksipolietilenglikolya c molecular weight of about 12000 and polyglutamic acid with the rate of polymerization of approximately 41 (176,5 mg)described in reference example 2 was dissolved in N,N-dimethylformamide (5.3 ml)was added 4-toluensulfonate complex benzyl ester of L-phenylalanine (63,0 mg), TFFH (38,9 mg), N,N-diisopropylethylamine (117,3 ml) and 2,5-di-tert-butyl-4-methylpyridine (87,0 mg) and stirred the mixture at 37°C for 22 hours. The reaction solution was cooled to room temperature, diluted with ethanol (10,6 ml) and with stirring was added dropwise diisopropyl ether (42,4 ml). The mixture was stirred is for 30 minutes, the precipitate was collected by filtration and washed with a mixed solvent consisting of diisopropyl ether and ethanol (4:1). The obtained product was dissolved in 20% aqueous solution of acetonitrile (16 ml) and deliberately distilled water (2 l × 3) through the dialysis membrane (cut-off molecular weight of from 12000 to 14000). Validirovannyj solution was passed through cation exchange resin Dowex 50W (proton type, 9 ml) and was suirable 50% aqueous solution of acetonitrile. Elyuirovaniya the fraction containing the desired compound were dried by freezing, while receiving specified in the header connection (194,0 mg).

The compound obtained hydrolyzed in the same way as in reference example 8, and produced quantitative determination of released benzyl alcohol using high-performance liquid chromatography (HPLC) in conditions similar to those specified in reference example 8, to measure the extent of binding of the amide bond group Phe-OBzl in the connection. As a result of measuring the degree of binding was determined as equal to 32.6% in terms of carboxyl group polyglutamine acid.

Reference example 10. Synthesis of amide conjugate complex benzyl ester of L-phenylalanine with N-acetylated by blockcopolymers monometoksipolietilenglikolya with a molecular weight of about 12000 and poliglota inovas acid with the rate of polymerization, approximately 32

The N-acetylated block copolymers monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization of approximately 32 (668 mg)described in reference example 4 was dissolved in N,N-dimethylformamide (13 ml), was added 4-toluensulfonate complex benzyl ester of L-phenylalanine (282 mg), TFFH (175 mg) and N,N-diisopropylethylamine (345 μl) and the mixture was stirred at 40°C for 20 hours. The reaction solution was cooled to room temperature, diluted with ethanol (26 ml) and with stirring was added dropwise diisopropyl ether (104 ml). The precipitate was collected by filtration and washed with a mixed solvent consisting of diisopropyl ether and ethanol (4:1). The obtained product was dissolved in 50% aqueous solution of acetonitrile (16 ml) and deliberately distilled water (2 l × 3) through the dialysis membrane (cut-off molecular weight of from 12000 to 14000). Validirovannyj solution was passed through cation exchange resin Dowex 50W (proton type, 10 ml) and was suirable 50% aqueous solution of acetonitrile. Elyuirovaniya the fraction containing the desired compound were dried by freezing, while receiving specified in the header connection (762 mg).

The compound obtained hydrolyzed in the same way as in reference example 8, and produced quantitative determination shall prolong released benzyl alcohol using high-performance liquid chromatography (HPLC) under the conditions same manner in reference example 8, to measure the extent of binding of the amide bond group Phe-OBzl in the connection. As a result of measuring the degree of binding was determined as equal to 41.9% in terms of carboxyl group polyglutamine acid.

Reference example 11. Synthesis of amide conjugate complex benzyl ester L-valine with N-acetylated by blockcopolymers monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization equal to approximately 36

The N-acetylated block copolymers monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization equal to approximately 36 (531 mg)described in reference example 5 was dissolved in N,N-dimethylformamide (10,6 ml), was added 4-toluensulfonate complex benzyl ester L-valine (195 mg), TFFH (135 mg) and N,N-diisopropylethylamine (288 μl) and the mixture was stirred at 40°C for 30 hours. The reaction solution was cooled to room temperature, diluted with ethanol (20 ml) and with stirring was added dropwise diisopropyl ether (80 ml). The mixture was stirred for 30 minutes, the precipitate was collected by filtration and washed with a mixed solvent consisting of diisopropyl ether and ethanol (4:1). The obtained product was dissolved in 30% in the bottom solution of acetonitrile (25 ml) and deliberately distilled water (2 l ×3) through the dialysis membrane (cut-off molecular weight of from 12000 to 14000). To validirovannoe solution was added cation exchange resin Dowex 50W (proton type, 3 ml)was stirred for 30 minutes and was filtered resin. The filtrate containing the desired compound were dried by freezing, while receiving specified in the title compound (559 mg).

The compound obtained hydrolyzed in the same way as in reference example 8, and produced quantitative determination of released benzyl alcohol using high-performance liquid chromatography (HPLC) in conditions similar to those specified in reference example 8, to measure the extent of binding of the amide bond group Val-OBzl in the connection. As a result of measuring the degree of binding was determined as equal to 41.3% in terms of carboxyl group polyglutamine acid.

Reference example 12. Synthesis of amide conjugate complex benzyl ester of L-phenylalanine with N-acetylated by blockcopolymers monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization of approximately 26

The N-acetylated block copolymers monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization equal to about 26 (6,00 mg)described in reference example 1 was dissolved in N,N-dimethylformamide (150 ml)was added Ki is rochloride complex benzyl ester of L-phenylalanine (2,08 mg), DMT-MM (2.37 mg) and N,N-diisopropylethylamine (1,24 μl) and the mixture was stirred at 40°C during the night. The reaction solution was cooled to room temperature and was added dropwise to a mixed solvent consisting of diisopropyl ether and ethanol (4:1, 1500 ml). The mixture was stirred for 30 minutes, the precipitate was collected by filtration and washed with a mixed solvent consisting of diisopropyl ether and ethanol (4:1). The obtained product was dissolved in 97 wt.% aqueous solution of DMF (150 ml), was added cation exchange resin Dowex 50W (proton type, 15 ml), the mixture was stirred at room temperature for 2 hours, the resin was filtered and washed with DMF (75 ml). The obtained filtrate was added dropwise to a mixed solvent consisting of diisopropyl ether and ethanol (4:1) (2400 ml)was stirred for 30 minutes and collected the resulting residue by filtration, thus obtaining specified in the header connection (to 6.88 g).

The compound obtained hydrolyzed in the same way as in reference example 8, and produced quantitative determination of released benzyl alcohol using high-performance liquid chromatography (HPLC) in conditions similar to those specified in reference example 8, to measure the extent of binding of the amide bond group Phe-OBzl in the connection. As a result, u is of the degree of binding was determined as equal to 62.4 per cent in terms of carboxyl group polyglutamine acid.

Reference example 13. Synthesis of ester conjugate of benzylbromide with N-acetylated by blockcopolymers monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization of approximately 26

The N-acetylated block copolymers monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization equal to about 26 (342 mg)described in reference example 1 was dissolved in N,N-dimethylformamide (6.8 ml), was added benzylbromide (29,0 μl) and N,N-diisopropylethylamine (53,1 μl) and stirred the mixture at 37°C over night. The reaction solution was cooled to room temperature, diluted with ethanol (to 13.6 ml) and with stirring was added dropwise diisopropyl ether (54,4 ml). The mixture was stirred for one hour, the precipitate was collected by filtration and washed with a mixed solvent consisting of diisopropyl ether and ethanol (4:1). The obtained product was dissolved in 50% aqueous solution of acetonitrile (20 ml), the solution was passed through cation exchange resin Dowex 50W (proton type, 4 ml) and was suirable 50% aqueous solution of acetonitrile. Elyuirovaniya the fraction containing the desired compound were concentrated under reduced pressure to 1/2 volume and dried by freezing, while receiving specified in sagola the ECS compound (352 mg).

The compound obtained hydrolyzed in the same way as in reference example 8, and produced quantitative determination of released benzyl alcohol using high-performance liquid chromatography (HPLC) in conditions similar to those specified in reference example 8, to measure the extent of binding of the amide bond group OBzl in the connection. As a result of measuring the degree of binding was determined as equal to 25.0% in terms of carboxyl group polyglutamine acid.

Reference example 14. Synthesis of ester conjugate 4-phenyl-butylbromide with N-acetylated by blockcopolymers monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization of approximately 26

The N-acetylated block copolymers monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization equal to about 26 (2,33 g)described in reference example 7, was dissolved in N,N-dimethylformamide (50 ml), was added 4-phenylbutyramide (682 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU, 598 μl) and the mixture was stirred at 38°C during the night. The reaction solution was cooled to room temperature and was added dropwise to a mixed solvent consisting of diisopropyl ether and ethanol (4:1, 500 ml). The mixture is stirred during one hour, the precipitate was collected by filtration and washed with a mixed solvent consisting of diisopropyl ether and ethanol (4:1). The obtained product was dissolved in 50% aqueous solution of acetonitrile, was added cation exchange resin Dowex 50W (proton type, 5 ml), the mixture was stirred for 2 hours, the resin was filtered and the filtrate was dried by freezing, while receiving specified in the header connection (2,54 g).

The compound obtained hydrolyzed in the same way as in reference example 8, and produced quantitative determination of released 4-phenylbutane using high-performance liquid chromatography (HPLC) to measure the extent of binding of 4-phenylbutazone group in the connection. As a result of measuring the degree of binding was determined as equal to 65.7% in terms of carboxyl group polyglutamine acid.

Example 1. Polymer derived antimetabolite of cytidine formula (1)in which R denotes a methyl group; a represents acetyl group; the average value of n is 272, average value of m is equal to 21 and X means gemcitabine or a hydroxyl group

N,N-Dimethylformamide (15 ml) and N,N-diisopropylethylamine (192 μl) was added to N-acetylated to blockcopolymer monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the index of the polymerization, approximately 21 (759 g)described in reference example 6, and gemcitabine hydrochloride (330 mg) and stirred at 37°C. After dissolution, the mixture was added 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline (EEDQ, 300 mg) and stirred at 37°C for 20 hours. The reaction solution was cooled to room temperature, diluted with ethanol (30 ml) and with stirring was added dropwise diisopropyl ether (120 ml). The mixture was stirred for one hour, the precipitate was collected by filtration and washed with a mixed solvent consisting of diisopropyl ether and ethanol (4:1). The obtained product was dissolved in 25% aqueous solution of acetonitrile (40 ml) and deliberately distilled water (2 l ×3) through the dialysis membrane (cut-off molecular weight of from 12000 to 14000). Validirovannyj solution was dried by freezing, while receiving specified in the header connection (1,078 mg).

The compound obtained hydrolyzed and produced quantitative determination of released gemcitabine using high-performance liquid chromatography (HPLC) to measure the content of gemcitabine in combination. As a result of the measurement the specified number was determined as equal to 20.8% (wt/wt) (58,0% in terms of carboxyl group of the polycarboxylic acid) in the form of gemcitabine hydrochloride. In addition, when the compound of the present invention was subjected to HPLC analysis, the content of free gemcitabine was equal to 0.3% or less.

The method of hydrolysis

Specified in the header connection (3,60 mg) was dissolved in methanol (0.5 ml)was added concentrated ammonia water (0.5 ml)was sealed and stirred at 37°C for one hour. The solution was neutralized with acetic acid and diluted with distilled water, getting exactly 10 ml.

Conditions of the analysis by HPLC analysis (gemcitabine):

column: Inertsil ODS-3 (particle size: 5 μm), diameter 4.6 x 150 mm;

the column temperature: 40°C;

eluent: 95% phosphate buffer (10 mm, pH 6.9) and 5% acetonitrile;

flow rate: 1 ml/min;

detector (wavelength detection): UV (275 nm).

Example 2. Polymer derived antimetabolite of cytidine formula (1)in which R denotes a methyl group; a represents acetyl group; the average value of n is 272, average value of m is equal to 24 and X is gemcitabine, a hydroxyl group or a residue of complex benzyl ester of L-phenylalanine

N,N-Dimethylformamide (26 ml) and N,N-diisopropylethylamine (0,213 ml) was added to the compound (1,298 g)described in reference example 8, and gemcitabine hydrochloride (0,366 g) and stirred at 37°C. After dissolution, the mixture was added 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline (EEDQ, 0,362 g) and stirred at 37°C over night. The reaction solution Oh what was Adali to room temperature, was diluted with ethanol (52 ml) and with stirring was added dropwise diisopropyl ether (208 ml). The mixture was stirred for one hour, the precipitate was collected by filtration and washed with a mixed solvent consisting of diisopropyl ether and ethanol (4:1). The obtained product was dissolved in 25% aqueous solution of acetonitrile (40 ml) and deliberately distilled water (2 l ×3) through the dialysis membrane (cut-off molecular weight of from 12000 to 14000). Validirovannyj solution was dried by freezing, while receiving specified in the header connection (1,330 g).

The compound obtained hydrolyzed in the same way as in example 1, and produced quantitative determination of released gemcitabine using high-performance liquid chromatography (HPLC) in conditions similar to those specified in example 1, to measure the content of gemcitabine in combination. As a result of the measurement the specified number was determined as equal to 10.7% (wt/wt) (28.1% in terms of carboxyl group of the polycarboxylic acid) in the form of gemcitabine hydrochloride. In addition, when the compound of the present invention was subjected to HPLC analysis, the content of free gemcitabine was equal to 0.3% or less.

Example 3. Polymer derived antimetabolite of cytidine formula (1), in which R means methyl gr the foam; And means acetyl group; the average value of n is 272, average value of m is equal to 41 and X means gemcitabine, a hydroxyl group or a residue of complex benzyl ester of L-phenylalanine

N,N-Dimethylformamide (3.3 ml) and N,N-diisopropylethylamine (39,2 ml) was added to the compound (165 g)described in reference example 9, and gemcitabine hydrochloride (67,4 mg) and stirred at 37°C. After dissolution, the mixture was added 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline (EEDQ, 56,0 mg) and stirred at 37°C for 23 hours. The reaction solution was cooled to room temperature, diluted with ethanol (6.6 ml) and with stirring was added dropwise diisopropyl ether (26,4 ml). The mixture was stirred for 30 minutes, the precipitate was collected by filtration and washed with a mixed solvent consisting of diisopropyl ether and ethanol (4:1). The obtained product was dissolved in 10% aqueous solution of acetonitrile (16 ml) and deliberately distilled water (2 l ×3) through the dialysis membrane (cut-off molecular weight of from 12000 to 14000). Validirovannyj solution was dried by freezing, while receiving specified in the title compound (183 mg).

The compound obtained hydrolyzed in the same way as in example 1, and produced quantitative determination of released gemcitabine using high-performance liquid chromate is graphy (HPLC) under the conditions such as the one outlined in example 1, to measure the content of gemcitabine in combination according to the present invention. As a result of the measurement the specified number was determined as equal to 21.2% (wt/wt) (42.6% in terms of carboxyl group of the polycarboxylic acid) in the form of gemcitabine hydrochloride. In addition, when the compound of the present invention was subjected to HPLC analysis, the content of free gemcitabine was equal to 0.3% or less.

Example 4. Polymer derived antimetabolite of cytidine formula (1)in which R denotes a methyl group; a represents acetyl group; the average value of n is 272, average value of m is equal to 26 and X means gemcitabine, a hydroxyl group, or benzyloxy

N,N-Dimethylformamide (6 ml) and N,N-diisopropylethylamine (63,1 ml) was added to the compound (295 g)described in reference example 13, and gemcitabine hydrochloride (108,5 mg) and stirred at 37°C. After dissolution, the mixture was added 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline (EEDQ, of 98.2 mg) and stirred at 37°C for 23 hours. The reaction solution was cooled to room temperature, diluted with ethanol (12 ml) and with stirring was added dropwise diisopropyl ether (48 ml). The mixture was stirred for 30 minutes, the precipitate was collected by filtration and washed with a mixed solvent sostojashie is from diisopropyl ether and ethanol (4:1). The obtained product was dissolved in 10% aqueous solution of acetonitrile (16 ml) and deliberately distilled water (2 l ×3) through the dialysis membrane (cut-off molecular weight of from 12000 to 14000). Validirovannyj solution was dried by freezing, while receiving specified in the title compound (334 mg).

The compound obtained hydrolyzed in the same way as in example 1, and produced quantitative determination of released gemcitabine using high-performance liquid chromatography (HPLC) in conditions similar to those specified in example 1, to measure the content of gemcitabine in combination according to the present invention. As a result of the measurement the specified number was determined as equal to 20.5% (wt/wt) (49.9 percent in terms of carboxyl group of the polycarboxylic acid) in the form of gemcitabine hydrochloride. In addition, when the compound of the present invention was subjected to HPLC analysis, the content of free gemcitabine was equal to 5.1%.

Example 5. Polymer derived antimetabolite of cytidine formula (1)in which R denotes a methyl group; a represents acetyl group; the average value of n is 272, average value of m is equal to 36 and X means gemcitabine, a hydroxyl group or a residue of complex benzyl ester L-valine

N,N-Dimethylformamide (10.3 ml) and N,N-diisopropylethylamine (77,9 ál) we use the and to the compound (515 mg), described in reference example 11, and gemcitabine hydrochloride (134 mg) and stirred at 40°C. After dissolution, the mixture was added 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline (EEDQ, 166 mg) and stirred at 40°C for 20 hours. The reaction solution was cooled to room temperature, diluted with ethanol (20,6 ml) and with stirring was added dropwise diisopropyl ether (82,4 ml). The precipitate was collected by filtration and washed with a mixed solvent consisting of diisopropyl ether and ethanol (4:1). The obtained product was dissolved in 30% aqueous solution of acetonitrile (20 ml) and deliberately distilled water (2 l ×3) through the dialysis membrane (cut-off molecular weight of from 12000 to 14000). Validirovannyj solution was dried by freezing, while receiving specified in the title compound (574 mg).

The compound obtained hydrolyzed in the same way as in example 1, and produced quantitative determination of released gemcitabine using high-performance liquid chromatography (HPLC) in conditions similar to those specified in example 1, to measure the content of gemcitabine in combination according to the present invention. As a result of the measurement the specified number was determined as equal to 14.1% (wt/wt) (28.8 per cent in terms of carboxyl group of the polycarboxylic acid) in the form of a hydrochloride is gemcitabine. In addition, when the compound of the present invention was subjected to HPLC analysis, the content of free gemcitabine was equal to 0.2% or less.

Example 6. Polymer derived antimetabolite of cytidine formula (1)in which R denotes a methyl group; a represents acetyl group; the average value of n is 272, average value of m is equal to 26 and X means gemcitabine, a hydroxyl group or a residue of complex benzyl ester of L-phenylalanine

N,N-Dimethylformamide (75 ml) and N,N-diisopropylethylamine (286 μl) was added to the compound (3.0 g)described in reference example 12, and gemcitabine hydrochloride (492 mg) and stirred at 40°C. After dissolution, the mixture was added 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline (EEDQ, 508 mg) and stirred at 40°C for 24 hours. The reaction solution was cooled to room temperature and was added dropwise to a mixed solvent consisting of diisopropyl ether and ethanol (4:1) (750 ml). The mixture was stirred for 30 minutes, the precipitate was collected by filtration and washed with a mixed solvent consisting of diisopropyl ether and ethanol (4:1). The obtained product was dissolved in 50% aqueous solution of acetonitrile (50 ml) and deliberately distilled water (3 l ×3) through the dialysis membrane (cut-off molecular weight of from 12000 to 14000). Validirovannyj solution sushi is whether freezing, while receiving specified in the header connection (2,94 g).

The compound obtained hydrolyzed in the same way as in example 1, and produced quantitative determination of released gemcitabine using high-performance liquid chromatography (HPLC) in conditions similar to those specified in example 1, to measure the content of gemcitabine in combination. As a result of the measurement the specified number was determined as equal to 4,67% (wt/wt) (11.9% in terms of carboxyl group of the polycarboxylic acid) in the form of gemcitabine hydrochloride. In addition, when the compound of the present invention was subjected to HPLC analysis, the content of free gemcitabine was equal to 0.2% or less.

Example 7. Polymer derived antimetabolite of cytidine formula (1)in which R denotes a methyl group; a represents acetyl group; the average value of n is 272, average value of m is equal to 26 and X means gemcitabine, a hydroxyl group or a residue of 4-phenylbutyramide alcohol

N,N-Dimethylformamide (50 ml) and N,N-diisopropylethylamine (218 μl) was added to the compound (2,07 g)described in reference example 14, and gemcitabine hydrochloride (375 mg) and stirred at 40°C. After dissolution, the mixture was added 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline (EEDQ, 386 mg) and stirred at 40°C for 24 hours. The reaction solution of ohlord is whether to room temperature and was added dropwise to a mixed solvent, consisting of diisopropyl ether and ethanol (4:1, 750 ml). The mixture was stirred for one hour, the precipitate was collected by filtration and washed with a mixed solvent consisting of diisopropyl ether and ethanol (4:1). The obtained product was dissolved in 50% aqueous solution of acetonitrile (25 ml) and deliberately distilled water (3 l ×3) through the dialysis membrane (cut-off molecular weight of from 12000 to 14000). Validirovannyj solution was dried by freezing, while receiving specified in the title compound (2.05 in).

The compound obtained hydrolyzed in the same way as in example 1, and produced quantitative determination of released gemcitabine using high-performance liquid chromatography (HPLC) in conditions similar to those specified in example 1, to measure the content of gemcitabine in combination according to the present invention. As a result of the measurement the specified number was determined as equal to 7.35% (wt/wt) (17.5% in terms of carboxyl group of the polycarboxylic acid) in the form of gemcitabine hydrochloride. In addition, when the compound of the present invention was subjected to HPLC analysis, the content of free gemcitabine was equal to 0.2% or less.

Example 8. Polymer derived antimetabolite of cytidine formula (1)in which R denotes a methyl group; And means the AET acetyl group; the average value of n is 272, average value of m is equal to 32 and X means cytarabine or hydroxyl group

The N-acetylated block copolymers monometoksipolietilenglikolya with a molecular weight of about 12000 and polyglutamic acid with the rate of polymerization of approximately 32 (130 mg)described in reference example 4, and cytarabine (50.0 mg) was dissolved in N,N-dimethylformamide (2.6 ml)was added 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline (EEDQ, of 63.6 mg) and stirred at 40°C for 24 hours. The reaction solution was cooled to room temperature, diluted with ethanol (5.2 ml) and with stirring was added dropwise diisopropyl ether (20,8 ml). The mixture was stirred for 30 minutes, the precipitate was collected by filtration and washed with a mixed solvent consisting of diisopropyl ether and ethanol (4:1). The obtained product was dissolved in 20% aqueous solution of acetonitrile and deliberately distilled water (2 l ×3) through the dialysis membrane (cut-off molecular weight of from 12000 to 14000). Validirovannyj solution was dried by freezing, while receiving specified in the title compound (143 mg).

The compound obtained hydrolyzed and produced quantitative determination of free citarabinom using high-performance liquid chromatography (HPLC) to measure the content is fully settled in to the connection. As a result of the measurement the specified number was determined as equal to 22.5% (wt/wt) (59,2% in terms of carboxyl group of the polycarboxylic acid) in the form of citarabinom.

The method of hydrolysis

Specified in the header connection (3,20 mg) was dissolved in methanol (0.5 ml)was added concentrated ammonia water (0.5 ml)was sealed and stirred at 37°C for one hour. The solution was neutralized with acetic acid and diluted with distilled water, getting exactly 10 ml.

Conditions of the analysis by HPLC (analysis tsitarabina):

column: SUPELCO Discovery HS F5 (particle size: 5 μm), the diameter of 4.6 × 250 mm;

the column temperature: 40°C;

eluent: phosphate buffer (10 mm, pH 6.9);

flow rate: 1 ml/min;

detector (wavelength detection): UV (275 nm).

Example 9. Polymer derived antimetabolite of cytidine formula (1)in which R denotes a methyl group; a represents acetyl group; the average value of n is 272, average value of m is equal to 32 and X means cytarabine, hydroxyl group or the residue of a complex benzyl ester of L-phenylalanine

The compound (267 mg)described in reference example 10, and cytarabine (50.0 mg) was dissolved in N,N-dimethylformamide (5.3 ml)was added 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline (EEDQ, of 63.6 mg) and stirred at 40°C for 21 hours. The reaction R is the target was cooled to room temperature, was diluted with ethanol (10,6 ml) and with stirring was added dropwise diisopropyl ether (42,4 ml). The mixture was stirred for 30 minutes, the precipitate was collected by filtration and washed with a mixed solvent consisting of diisopropyl ether and ethanol (4:1). The obtained product was dissolved in 30% aqueous solution of acetonitrile and deliberately distilled water (2 l ×3) through the dialysis membrane (cut-off molecular weight of from 12000 to 14000). Validirovannyj solution was dried by freezing, while receiving specified in the title compound (290 mg).

The compound obtained hydrolyzed in the same way as in example 8, and produced quantitative determination of free citarabinom using high-performance liquid chromatography (HPLC) in conditions similar to those specified in example 8, for measuring the content of citarabinom in the connection. As a result of the measurement the specified number was determined as equal to 11.3% (wt/wt) (31.5% in terms of carboxyl group of the polycarboxylic acid) in the form of citarabinom.

Test example 1. Study of release of drugs in the absence of enzyme

The compound of example 1 (indicated as compound 1 in figure 1), the compound from example 2 (indicated as compound 2 in figure 1) or the compound from example 7 (indicated as the connection is giving 7 in figure 1) was dissolved in physiological solution with phosphate buffer (pH 7.4) to achieve concentrations, equal to 1.0 mg/ml and left to stand at a constant temperature equal to 37°C. the Amount of released gemcitabine was measured depending on time using HPLC to determine the percentage of the number of released gemcitabine in terms of the total number of gemcitabine used in the connection. The obtained results are shown in figure 1. As a result of the study it was found that the compounds of the present invention slowly release the drug regardless of the enzyme.

Test example 2. Study of the release of the drug in the plasma of mice

The compound of example 1 (2.3 mg; listed as compound 1 in figure 2) or the compound from example 2 (3.7 mg; listed as compound 2 in figure 2) was dissolved in physiological solution with phosphate buffer (0.1 ml, pH 7.4), was added 4-fold amount (V/V) plasma (0.4 ml)obtained in mice, and leave the mixture to stand at a constant temperature equal to 37°C. over a certain period of time, taking aliquots in the amount of fifty microlitres and diluted 50% aqueous solution of methanol (450 ml). The solution was deproteinization using a membrane filter (pore size: 0.45 μm), and measured the amount of released gemcitabine using HPLC to determine the percentage of mn is in the number of released gemcitabine in terms of the total number of gemcitabine used in the connection. The obtained results are shown in figure 2. It was found that the compounds of the present invention also slowly release the drug in plasma.

Test example 3. Antitumor effect in mice suffering from cancer (1)

In mice caused a carcinoma of the colon by serial subcutaneous implantation of tumor mice Colon 26. Tumor Colon 26 was cut into square pieces of about 2 mm and the resulting fragments tumors subcutaneously implanted in mice by trocar. Seven days after implantation of tumor compound of example 1 (indicated as compound 1 in table 2), the compound from example 2 (indicated as compound 2 in table 2), the compound from example 4 (indicated as compound 4 in table 2) and gemcitabine hydrochloride as a control tool was dissolved in 5% injectable solution of glucose, after which each compound or control vehicle was administered intravenously once at the doses indicated in table 2. Tumor size was measured on the day of injection and on day 7 after administration of the medicinal product and calculated volumes of tumors using the following equation. The relative volumes of the tumors were determined 7 days after injection compared with the first day of injection. The results are shown in table 2.

Equation 1

Table 2
MedicationDose (gemcitabine hydrochloride) (mg/kg)Relative tumor volume*
The absence of the treatment08,8±4,9
Connection 1500,4±0,2
251,5±0,5
Connection 212,50,5±0,3
6,252,4±1,1
Connection 4250,5±0,1
6,253,6±0,5
Control tool2001,4±0,1
1002,6±0,7
* The average relative tumor volume (mean ± standard deviation (SD)) after 7 days after the beginning of the introduction given the fact that the tumor volume on the first day of introduction which was set equal to 1.0.

The results imply that the compounds of the present invention have equivalent or higher antitumor effect at lower doses compared with gemcitabine hydrochloride, used as a control means. In addition, it was found that the compound of the present invention, containing a hydrophobic substituent (compound according to example 2 or 4), has a comparable effect at lower doses compared with the connection, not having hydrophobic substituent (compound of example 1).

Test example 4. Antitumor effect in mice with cancer (2)

In mice caused a carcinoma of the colon by serial subcutaneous implantation of tumor mice Colon 26. Tumor Colon 26 was cut into square pieces of about 2 mm and the resulting fragments tumors subcutaneously implanted in mice by trocar. Seven days after implantation of tumor compound from example 7 (indicated as compound 7 in table 3) and gemcitabine as a control tool was dissolved in 5% injectable glucose solution and injected intravenously once at the dosages indicated in table 3. The volume of tumors was calculated on the day of injection and on day 10 after administration of the medicinal product in accordance with the description given is authorized in test example 3. The relative volumes of the tumors were determined 10 days after injection compared with the first day of injection. The results are shown in table 3.

Table 3
MedicationDose (gemcitabine hydrochloride) (mg/kg)Relative tumor volume*
The absence of the treatment010,5±5,0
Connection 7250,3±0,3
16,7was 1.1±0.5
Control tool2003,4±0,6
1003,9±0,5
* The average relative tumor volume (mean ± standard deviation (SD)) after 7 days after the beginning of the introduction given the fact that the tumor volume on the first day of injection was set equal to 1.0.

The results imply that the compound of the present invention has equivalent or higher antitumor effect at lower dose is compared with gemcitabine hydrochloride, used as a reference tool.

Test example 5. Antitumor effect in mice with cancer (3)

In mice caused a carcinoma of the colon by serial subcutaneous implantation of tumor mice Colon 26. Tumor Colon 26 was cut into square pieces of about 2 mm and the resulting fragments tumors subcutaneously implanted in mice by trocar. Seven days after implantation of tumor compound from example 8 (indicated as compound 8 in table 4), the compound from example 9 (indicated as compound 9 in table 4) and cytarabine as a control tool was dissolved in 5% injectable solution of glucose, after which each compound or control vehicle was administered intravenously once at the dosages indicated in table 4. The volume of tumors was calculated on the day of injection and on day 10 after administration of the medicinal product in accordance with the description given in test example 3. The relative volumes of the tumors were determined 10 days after injection compared with the first day of injection. The results are shown in table 4.

Table 4
MedicationDose (citarabinom) (mg/kg) Relative tumor volume*
The absence of the treatment010,4±4,0
Compound 82006,9±1,3
1009,4±2,8
Connection 91505,7±1,5
1006,4±0,5
Control tool16008,4±2,9
80010,0±3,3
100×5**9,0±2,0
* The average relative tumor volume (mean ± standard deviation (SD)) within 10 days after the beginning of the introduction given the fact that the tumor volume on the first day of injection was set equal to 1.0.
** Continuous infusions for five days at a dose of 100 mg/kg

The results imply that the compounds of the present invention have a stronger antitumor effect at lower doses compared with citarabinom used as a control means. In addition, it was the mouth of the lished, what compound containing hydrophobic substituent (compound according to example 9), has a comparable effect at lower doses compared with the connection, not having hydrophobic substituent (compound according to example 8).

1. Polymer derived antimetabolite of cytidine, in which the structure of the amino antimetabolite of cytidine linked by an amide bond with a carboxyl group in the side chain polymeric compounds consisting of polietilenglikoli parts and circuit polyglutamine acid, while the above derivative is a compound expressed by the General formula (1):
Formula 1

where R means a hydrogen atom or C1-C6 alkyl group; a represents a hydrogen atom, C1-C6 acyl group, or C1-C6 alkoxycarbonyl group; m denotes a number from 3 to 200 as an average value; n denotes a number from 5 to 2000 average value; x is the residue of the antimetabolite of cytidine, a hydroxyl group or a hydrophobic Deputy, and X means the rest of the antimetabolite of cytidine in the amount of 3-100% m hydroxyl group in the amount of 0-95% m and hydrophobic substituent in the amount of 0-80% m, and where the rest of the antimetabolite of cytidine means a group expressed by the formula (2):
Formula 2

where Z means a hydrogen atom or a fluorine atom; Rf group means is, selected from the group consisting of substituents of formula (3):
Formula 3

and where hydrophobic Deputy means derived α-amino acids expressed by the formula (4):
Formula 4

where Q denotes a side chain of a neutral amino acid; W stands for C1-C6 alkyl group or a benzyl group; or a group expressed by the formula (5):
Formula 5

where T denotes C1-C6 alkyl group optionally substituted phenyl group.

2. Polymer derived antimetabolite of cytidine according to claim 1, in which R is C1-C3 alkyl group; a represents C2-C4 acyl group; and m denotes a number from 5 to 100 as an average value; n represents the number from 50 to 1000 as an average value.

3. Polymer derived antimetabolite of cytidine according to claim 1, in which R denotes a methyl group; a represents acetyl group; and m denotes a number from 10 to 60 as an average value; n represents the number from 100 to 300 as an average value; x is the residue of the antimetabolite of cytidine or hydroxyl group; and an antimetabolite of cytidine means cytarabine, gemcitabine or 5'-deoxy-5-perltidy.

4. Polymer derived antimetabolite of cytidine according to claim 1 or 2, in which Q means ISO-propyl group or a benzyl group, and W means a benzyl group.

5. The floor is measured derived antimetabolite of cytidine according to claim 1 or 2, where T means a benzyl group, 3-phenylpropyl group, 4-phenylbutyl group or 5-phenylmethylene group.

6. Polymer derived antimetabolite of cytidine according to claim 1, in which R denotes a methyl group; a represents acetyl group; and m denotes a number from 10 to 60 as an average value; n represents the number from 100 to 300 as an average value; an antimetabolite of cytidine means cytarabine, gemcitabine or 5'-deoxy-5-perltidy and hydrophobic Deputy means benzyloxy, 4-fenilbutazonu group, (1-benzyloxycarbonyl-2-methyl)propylamino or (1-benzyloxycarbonyl-2-phenyl)ethylamino.

7. Antitumor agent containing polymer derived antimetabolite of cytidine according to any one of claims 1 to 6, as a medicinal component.

8. A method of obtaining a polymer derived antimetabolite of cytidine according to any one of claims 1 to 6, which includes linking amide bond using the agent for dehydrocondensation selected from the group consisting of (chloride of 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine) and 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline, in an organic solvent, the amino group of the antimetabolite cytidine, the balance of which is characterized in claim 1, with a carboxyl group in the side chain of the polymer compound of formula (1) according to claim 1, where X means a hydroxyl gr the PPU, consisting of polietilenglikoli part and the polymer part containing carboxyl groups in the side chains.



 

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22 cl, 1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of existing and novel N-sulfamoyl- N'-arylpiperazines and their physiologically compatible acid-addition salts of formula I , where Ar denotes a monocyclic or bicyclic C6-C10aryl in which ring carbon atoms are optionally substituted with 1-3 nitrogen or oxygen atoms, and/or where the C6-C10aryl ring system optionally contains 3-5 double bonds, and/or where the C6-C10aryl ring system is optionally substituted with 1 or 2 substitutes which can be identical or different and which can be selected from a group containing halogen, trifluoromethyl, cyano group, nitro group, C1-C4alkyl, C1-C4alkoxy group, C1-C4alkylsulfonyl; and two oxygen atoms which are bonded to two neighbouring carbon atoms of the C6-C10aryl ring system and are bonded by a C1-C2alkylene bridge; or where the C6-C10aryl ring system is substituted with phenyl which can optionally be substituted in the phenyl ring by one substitute which can be selected from a group containing halogen; for preventing or treating obesity and related diseases.

EFFECT: design of a method of obtaining the said compounds and a pharmaceutical composition based on the said compounds.

25 cl, 9 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of the formula (I) R is radical selected out of i) , ii) , iii) , iv) , where R7 is halogen, cyano, C1-4alkyl, C1-4alkoxy; p is integer within 0 to 3; R1 is hydrogen, C2-4alkenyl or C1-4alkyl; R2 is hydrogen or C1-4alkyl; R3 and R4 are independently hydrogen or C1-4alkyl; R5 is: phenyl substituted with 1-3 groups selected independently out of trifluoromethyl, C1-4alkyl, cyano or halogen; naphthyl substituted with 1-3 groups selected independently out of trifluoromethyl, C1-4alkyl, cyano or halogen; benzofurane substituted with 1-3 groups selected independently out of C1-4alkyl or halogen; R6 is hydrogen or (CH2)qR8; R8 is hydrogen; m is zero or 1; n is 1; q is an integer within 1 to 4; r is 1 or 2; provided that if R5 is phenyl substituted with 1-3 groups selected independently out of trifluoromethyl, C1-4alkyl, cyano or halogen, then R is not radical i) ; and pharmaceutically acceptable salts or solvates thereof. The invention also refers to method (A) of compound obtainment, to compound application, to pharmaceutical composition, as well as to mammal treatment method.

EFFECT: obtainment of novel bioactive compounds with tachykinin receptor antagonist activity.

16 cl, 116 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds - 5-[3-(4-benzyloxyphenylthio)-fur-2-yl]-imidazolidine-2,4-diones and their formula (IV) or pharmaceutically acceptable salts thereof , where R is selected from a group consisting of phenyl, 4-benzyloxyphenyl, 4-diphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl and 3-trifluoromethylphenyl, useful as human microphage elastase (MMP-12) inhibitors, as well as pharmaceutical compositions based on the said compounds and inhibition method.

EFFECT: obtaining compounds useful as human microphage elastase (MMP-12) inhibitors, as well as design of pharmaceutical compositions based on the said compounds and inhibition method.

6 cl, 1 dwg,1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: described is a compound selected from a group consisting of formula II formula III and formula IV , or its salt or ester, where G1 is selected from a group which includes - (CR1R2)n-, n equals 0 or 1; R1 and R2 are independently selected from a group which includes hydrogen; X1, X2 and X3 are independently selected from a group consisting of hydrogen, optionally substituted lower alkyl, halogen, optionally substituted lower alkoxy, G2 is a heterocycloalkyl linker optionally substituted with X4 and X5, where the heterocycloalkyl linker is selected from a group consisting of piperazinyl, 3,6-dihydro-2N-pyridinyl, [1,4]diazepanyl, 3,9-diazabicyclo[3,3,1]nonyl; X4 and X5 are independently selected from a group consisting of hydrogen and optionally substituted lower alkyl; CO2R; R is selected from a group consisting of optionally substituted lower alkyl and hydrogen; G3 is a bond; G4 is selected from a group consisting of hydrogen, aryl, selected from phenyl which is optionally substituted with a lower alkyl, halogen, lower haloalkyl or lower haloalkoxy; heteroaryl selected from pyridinyl which is optionally substituted with a halogen or lower haloalkyl; and optionally substituted cycloheteroalkyl selected from 1,3-benzodioxolyl. Described also are specific compounds and a pharmaceutical composition.

EFFECT: disclosed compounds are used as modulators of receptors activated by a peroxisomal proliferator.

5 cl, 2 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: proposed phosphodiesterase 4 inhibitors are characterised by formulae II, III, V, VI, where X is CH or N; L is a single bond, -(CH2)nCONH-, -(CH2)nCON(CH2CH3)-, (CH2)nSO2, (CH2)nCO2 or alkylene, optionally substituted oxo or hydroxy; n assumes values from 0 to 3; R1 is optionally substituted alkyl; R3 - H, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted phenyl, phenylalkyl, heterocyclyl, heterocyclylalkyl or cycloalkylalkyl; R4 and R5 represent alkyl; R6 - cycloalkyl, R7 is H; R8 is H, carboxy, alkoxycarbonyl, -CO-alkyl, optionally substituted alkyl.

EFFECT: new phosphodiesterase 4 inhibitors have improved properties.

55 cl, 30 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula , where R1 is -O-X, where X is -(CH2)m-(CR9R10)p-(CH2)n-Z-(CH2)q-W, where m, n and q are independently equal to zero or assume values from 1 to 5; p equals 0 or 1; R9 and R10 are independently hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or cycloalkyl; or R9 and R10 together represent alkylene, which together with the carbon atom to which the are bonded, form an aryl; Z is a bond or O, W is aryl; R2 is hydrogen; L is a bond; R3 is hydrogen; R4 is hydrogen; R5 and R6 are independently hydrogen; R7 is hydrogen, halogen, hydroxy, trifluromethyl, lower alkyl, lower alkoxy, alkanoyl, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, acylamino, carbamoyl, carboxy, alkoxycarbonyl; or R5 and R6 together represent -(CH2)1-2-; Y is -(CH2)r-, -O-(CH2)r, -(CH2)r-O-, where r equals zero or assumes values from 1 to 3; Q together with atoms to which it is bonded form an aryl, pyridyl, pyrimidinyl, thienyl, furyl, pyrroliyl or indolyl ring; or to its pharmaceutically acceptable salts. The invention also relates to a method of inhibiting rennin activity in mammals, to a pharmaceutical composition, as well as to application.

EFFECT: obtaining new biologically active compounds with inhibitory activity towards renin.

23 cl, 52 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds exhibiting antiproliferative activity of formula (1) where W means N or C-R2; X means -NH-; Y means CH; Z means halogen, -NO2, C2-C3alkynyl-, halogen-C1-C3alkyl- and -C(=O)-C1-C3alkyl, A means a group of formula (i), (ii) or (iii) Q1 means phenyl; B1, B2, B3 and B4 independently mean C-RgRh, N-Ri or O; R1 means hydrogen; R2 means a residue specified from the group including hydrogen, halogen and -OR4; Ra, Rb, Rc, Rd, Re and Rf independently mean hydrogen; Rg and Rh independently mean a residue specified from the group including hydrogen, =O, -OR4 and -NR4C(=O)R5; or mean optionally a residue monosubstituted or twice-substituted with equal or different substitutes and specified from the group including C1-C6alkyl and phenyl, the substitute/substitutes is/are specified from the group including R8/, -OR4, -C(=O)R4, -C(=O)OR4 and -C(=O)NR4R5 where R8/ and other values of radicals are specified in the patent claim, optionally in the form of their pharmacologically noncontaminating acid addition salts. The invention also concerns a pharmaceutical composition.

EFFECT: new compounds have effective biological properties.

8 cl, 6 dwg, 1086 ex

FIELD: medicine.

SUBSTANCE: invention discloses use of nanoparticles containing a matrix of at least one protein containing at least one anti-tumour active substance for preparing a medicinal agent for treating tumours whose resistance to chematherapeutic agents is associated with hyperexpression of P-glycoprotein, wherein the protein matrix includes at least one anti-tumour active substance which is not covalently bonded to said proteins.

EFFECT: doxorubicin nanoparticles in the disclosed medicinal agent and doxorubicin solution had comparable effect on non-resistant neuroblastoma cells; when resistance arose during therapy with cytostatic doxorubicin nanoparticles, the solution and liposomal preparation of doxorubicin were more effective in the disclosed agent.

4 cl, 2 dwg, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology. The compound- conjugate antibody-medicinal agent is proposed with formula I: Ab-(L-D)p, where one or more molecules of maytanazoid medicinal agents (D) are covalently binded by L to the antibody huMAb4D5-8 (Trastuzumab) (Ab), which binds to the HER2 receptor and inhibits tumor cell growth, overexpressing HER2 receptor.

EFFECT: also a pharmaceutical composition is proposed which contains the specified compound, and a method of treating malignant tumor using this composition.

20 cl, 8 tbl, 10 ex, 17 dwg

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