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Method of synthesis of anticancer derivatives of (poly)aminoalkylaminoacetamide epipodofillotoxine
Method of synthesis of anticancer derivatives of (poly)aminoalkylaminoacetamide epipodofillotoxine
IPC classes for russian patent Method of synthesis of anticancer derivatives of (poly)aminoalkylaminoacetamide epipodofillotoxine (RU 2450009):
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Carbocyclic and heterocyclic arylsulfones as γ-secretase inhibitors Carbocyclic and heterocyclic arylsulfones as γ-secretase inhibitors / 2448964
Claimed invention relates to compounds of formula (I) or to their pharmaceutically acceptable salts, in which X is selected from group, consisting of-C(R1)2-, -O-, -S-, -S(O2)-, -NR1-; each R1 is independently selected from group consisting of H and alkyl; each of R2, R3 and R4 is independently selected from group consisting of (1) H, (2) alkyl, (3) -OR5, (4) alkylene-OR5, (5) -alkylene-R6, (6) -C(O)O-alkyl, (7) - alkylene-C(O)O-alkyl, (8) -alkylene-R8, (9) -NHR5, (10) -N(R5)2, (11) alkenyl, (12) -NH-R8, (13) -NH-CH(C(O)O(C1-C6)alkyl)-alkylene-O-alkyleneR6, (14)-NHCH(C(O)O(C1-C6)aalkyl)-alkylene-OH, (15) -NH-C(O)-alkenyl and (16) -N(C1-C6alkyl)C(O)-alkenyl; or R2 and R3 or R2 and R4 or R3 and R4 together with atoms with which they are bound, form condensed 3-7-member cycloalkyl or heterocycloalkyl ring, which represents non-aromatic monocyclic ring system, which contains in ring from about 5 to about 7 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen or oxygen, and said condensed cycloalkyl or heterocycloalkyl ring is not substituted or is substituted with one or several groups L3 ; and on condition that if X represents -O-, and m equals 1, then, at least, one of R2, R3 or R4 is not H; each R5 is independently selected from group consisting of (1) H, (2) (C1-C6)alkyl, (3) hydroxy-substituted alkyl, (4) R6, (5) R7, (6) -C(O)-(C1-C6)alkyl, (7) -C(O)-(C1-C6)halogenalkyl, (8) -C(O)-R6, (9) -C(O)-R7, (10) -C(O)NH-(C1-C6)alkyl, (11) -C(O)N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (12) -S(O)2-(C1-C6)alkyl, (13) -S(O)2-(C1-C6)halogenalkyl, (14) -S(O)2-R6, (15) -S(O)2-R7, (16) -S(O)2-R8, (17) -alkylene-C(O)-(C1-C6)alkyl, (18) -alkylene-C(O)-(C1-C6)halogen-alkyl, (19) -alkylene-C(O)-R6, (20) -alkylene-C(O)-R7, (21) -alkylene-S(O)2-(C1-C6)alkyl, (22) -alkylene-S(O)2-(C1-C6)halogenalkyl, (23) -alkylene-S(O)2-R6, (24) -alkylene-S(O)2-R7, (25) -alkylene-S(O)2-R8, (26) -alkylene-NHC(O)-(C1-C6)alkyl, (27) -alkylene-NHC(O)-(C1-C6)halogenalkyl, (28) alkylene-NHC(O)-R6, (29) -alkylene-NHC(O)-R7, (30) -alkylene-NHS(O)2-(C1-C6)alkyl, (31) -alkylene-NHS(O)2-(C1-C6)halogenalkyl, (32) -alkylene-NHS(O)2-R6, (33) -alkylene-NHS(O)2-R7, (34) -alkylene-N(alkyl)C(O)-(C1-C6)alkyl, (35) -alkylene-N(alkyl)C(O)-(C1-C6)halogenalkyl, (36) -alkylene-N(alkyl)C(O)-R6, (37) -alkylene-N(alkyl)C(O)-R7, (38) -alkylene-N(alkyl)S(O)2-(C1-Ce)alkyl, (39) -alkylene-N(alkyl)S(O)2-(C1-C6)halogen-alkyl, (40)-alkylene-N(alkyl)S(O)2-R6, (41) -alkylene-N(alkyl)S(O)2-R7, (42) -alkylene-C(O)-NH-(C1-C6)alkyl, (43) -alkylene-C(O)-NHR6, (44) -alkylene-C(O)-NHR7, (45) -alkylene-S(O)2NH-(C1-C6)alkyl, (46) -alkylene-S(O)2NH-R6, (47) -alkylene-S(O)2NH-R7 , (48) -alkylene-C(O)-N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (49) -alkylene-C(O)-N(alkyl)-R6, (50) -alkylene-C(O)-N(alkylene)-R7, (51) -alkylene-S(O)2N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (52) -alkylene-S(O)2N(alkyl)-R6, (53) -alkylene-S(O)2N(alkyl)-R7, (54) -alkylene-OH, (55) -alkylene-OC(O)-NH-alkyl, (56) -alkylene-OC(O)NH-R8, (57) -alkylene-CN, (58) -R8, (59) -alkylene-SH, (60) -alkylene-S(O)2-NH-R8, (61) -alkylene-S(O)2-alkylene-R6, (62) substituted with halogen alkylene, (63) -C(O)OR8, (64) -C(O)O(C1-C6)alkyl, (65) -C(O)R8, (66) -C(O)-alkylene-O-(C1-C6)alkyl, (67) -C(O)NH2, (68) -alkylene-O-(C1-C6)alkyl, (69) -alkylene-R8, (70) -S(O)2-halogen(C1-C6)alkyl, (71) hydroxy-substituted halogen(C1-C6)alkyl, (72) -alkylene-NH2, (73) -alkylene-NH-S(O)2-R8, (74) -alkylene-NH-C(O)-R8, (75) -alkylene-NH-C(O)O-(C1-C6)alkyl, (76) -alkylene-O-C(O)-(C1-C6)alkyl, (77) -alkylene-O-S(O)2-(C1-C6)alkyl, (78) -alkylene-R6 , (79) -alkylene-R7, (80) -alkylene-NH-C(O)NH-(C1-C6)alkyl, (81) -alkylene-N(S(O)2 halogen(C1-C6)alkyl)2, and each -S(O)2 halogen(C1-C6)alkyl fragment is selected independently, (82) -alkylene-N((C1-C6)alkyl)S(O)2-R8 , (83) -alkylene-OC(O)-N(alkyl)2, and each alkyl is selected independently, (84) -alkylene-NH-(C1-C6)alkyl, (85) -C(O)-alkylene-C(O)O-(C1-C6)alkyl, (86) -C(O)-C(O)-O-(C1-C6)alkyl, (87) -C(O)-alkylene-R6, (88) -C(O)-NH-R8, (89) -C(O)-NH-R6, (90) -C(O)-NH-alkylene-R6, (91) -C(O)-alkylene-NH-S(O)2-halogen(C1-C6)alkyl, (92) -C(O)-alkylene-NH-C(O)-O-(C1-C6)alkyl, (93) -C(O)-alkylene-NH2, (94) -C(O)-alkylene-NH-S(O)2-R8, (95) -C(O)-alkylene-NH-S(O)2-(C1-C6)alkyl, (96) -C(O)-alkylene-NH-C(O)-(C1-C6)alkyl, (97) -C(O)-alkylene-N(S(O)2(C1-C6)alkyl)2, and each -S(O)2(C1-C6)alkyl fragment is elected independently, (98) -C(O)-alkylene-NH-C(O)-NH-(C1-C6)alkyl, (99) -alkylene-O-R6, (100) -alkylene-R7, (101) -C(O)OH, (102) -alkylene-N(S(O)2(C1-C6)alkyl)2, (103) -alkylene-C(O)-O-(C1-C6)alkyl, (104) halogenalkyl, (105) halogen, (106) -alkylene-C(O)-NH2, (107) =N-O-(C1-C6)alkyl, (108) =N-O-alkylene-R6, (109) =N-O-alkenyl, (110) -N-O-R6, (111) =N-NH-S(O)2-R6, (112) alkenyl, (113) =R8, (114) -O-C(O)-R9, (115) -O-C(O)-(C1-C6)alkyl, (116)-CN, R6 is selected from group consisting of unsubstituted (C6-C14)aryl, (C6-C14)aryl, substituted with one or several groups L1, unsubstituted (C5-C14)heteroaryl and (C5-C14)heteroaryl, which represents aromatic monocyclic or bicyclic system, which contains in ring from about 5 to about 9 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen or sulphur, one or in combination, substituted with one or several groups L1; R7 is selected from group consisting of unsubstituted heterocycloalkyl and heterocycloalkyl which represents non-aromatic monocyclic system, which contains in ring from about 4 to about 6 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen substituted with one or several groups L2; R8 is selected from group consisting of unsubstituted cycloalkyl and cycloalkyl substituted with one or several groups L2; A8 is selected from group consisting of (a) unsubstituted aryl, (b) aryl substituted with one or several groups L1; each group L1 is independently selected fron group consisting of halogen, alkyl, -CN, -CF3, -O-(C1-C6)alkyl, -O-(halogen(C1-C6)alkyl), -alkylen-OH (-CH2OH); each group L2 is independently selected from group consisting of (a) -OH, (b) alkyl, (c) alkyl substituted with one or several groups -OH and (d) piperidyl; each group L3 is independently selected from group consisting of -CN, =O, R5 , -OR5 ; =N-R5 and -N(R5)2; n equals 0, 1, 2 or 3; and m equals 0, 1 or 2; and on condition that in composition of substituent -OR5 fragment R5 and oxygen atom, which it is bound with, do not form group -O-O-; and on condition that in composition of substituents -OR5, =N-R5 and -NHR5 R5 are not -CH2OH, -CH2NH2, -CH2NH-alkyl, -CH2NH-aryl or -C(O)OH. Invention also relates to pharmaceutical composition, as well as to application of one or several compounds by one of ii. 1-125.
Synergist for improvement of effectiveness of biological agents against colorado potato beetle Synergist for improvement of effectiveness of biological agents against colorado potato beetle / 2448464
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Pharmaceutical salts of aminobicyclo[2,2,1]heptane as nf-kb transcription factor inhibitors with antiviral activity (versions) and using them Pharmaceutical salts of aminobicyclo[2,2,1]heptane as nf-kb transcription factor inhibitors with antiviral activity (versions) and using them / 2448692
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Pharmaceutical salts of aminobicyclo[2,2,1]heptane as nf-kb transcription factor inhibitors with antiviral activity (versions) and using them Pharmaceutical salts of aminobicyclo[2,2,1]heptane as nf-kb transcription factor inhibitors with antiviral activity (versions) and using them / 2448692
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Amine antioxidants for lubricating oil and motor fuel and production methods thereof Amine antioxidants for lubricating oil and motor fuel and production methods thereof / 2446147
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Antioxidants and methods of producing antioxidants / 2445349
Disclosed is a method of producing an antioxidant for lubricants, consisting of oligomers of alkylated diphenylamine and alkylated phenyl-α-naphthylamine, and a metal acetylacetonate, where the metal is Co (III), Co (II), Mn (II) or a combination thereof, involving mixing said components to form a reaction mixture and passing an oxygen-containing gas through the reaction mixture. Disclosed also is a method of producing a lubricant and a method of obtaining a lubricant formulation using an antioxidant obtained using said method.
Antioxidants and methods of producing antioxidants / 2445349
Disclosed is a method of producing an antioxidant for lubricants, consisting of oligomers of alkylated diphenylamine and alkylated phenyl-α-naphthylamine, and a metal acetylacetonate, where the metal is Co (III), Co (II), Mn (II) or a combination thereof, involving mixing said components to form a reaction mixture and passing an oxygen-containing gas through the reaction mixture. Disclosed also is a method of producing a lubricant and a method of obtaining a lubricant formulation using an antioxidant obtained using said method.
Compounds, method for preparing compound, pharmaceutical composition Compounds, method for preparing compound, pharmaceutical composition / 2244709
Invention describes compound of the formula (I):

FIELD: medicine.

SUBSTANCE: invention refers to a new method for preparing anticancer preparations representing derivatives of (poly)aminoalkylaminoacetamide epipodofillotoxine of formula 1. The method implies a condensation stage of the compounds of formulae 4 and 6 in a polar aprotonic solvent without pre-protection of functional amine groups to produce a compound of formula 1, wherein in formulae 1, 4 and 6 R represents hydrogen atom or -(CH2)c-NH2, 2≤a, b, c≤5.

EFFECT: what is offered is the new effective method for preparing the compounds with anticancer activity.

15 cl, 3 ex

 

The aim of the present invention is a new method of obtaining derivatives of (poly)aminoalkylated of epipodophyllotoxin formula 1 and their pharmaceutically acceptable salts.

Formula 1

in which R represents a hydrogen atom or a group -(CH2)with-NH2when 2≤a,b,c≤5.

These compounds consist of a linear fragment type epipodophyllotoxin and polyamino fragment associated with 4 position epipodophyllotoxin through acetamide link.

The presence polyamines chain attached properties water solubility to the molecule, in particular its chlorhydrate and pharmacological properties, particularly interesting in the treatment of cancer.

These compounds, as described in the application WO 2005/100363, are anti-cancer compounds that are particularly useful for the treatment of solid tumors, or not solid tumors, such as melanoma, colon cancer, prostate, bladder, breast, uterus, stomach, pancreas, liver, ovarian, and also for the treatment of leukemia, lymphoma and myeloma, cancer of the field ALL (ORL) and brain tumors.

In the method of synthesis described in WO 2005/100363, to obtain compounds of formula 1 as the starting compound used podophyllotoxin formula 2:

Formula 2

then 4'-demeti epipodophyllotoxin formula 3:

Formula 3

which is influenced by chloroacetonitrile in an acidic environment, obtaining an intermediate product for the synthesis of 4-chloroacetamido-4'-demethylepipodophyllotoxin formula 4:

Formula 4

Then this compound condenses with the reactant primary amine of formula 5:

Formula 5

in which R' represents hydrogen, or chain -(CH2)with-NHP, and in which R represents a protective group for the amine functional groups.

Suitable protective group can be a radical: benzyl, benzyloxycarbonyl or tertbutoxycarbonyl. This condensation is carried out in a solvent mixture comprising a polar aprotic solvent (acetonitrile, DMF) in the presence of a base Lewis (triethylamine).

However, this method, besides the fact that it includes an increased number of stages and, therefore, is rather low total yield is two inconveniences.

On the one hand, the terms used in the patent WO 2005/100363, favor the epimerization of the carbon atom in the 2 position derived epipodophyllotoxin formula 1, leading to the form of the CIS-lactone, titled micro", formula 7:

Formula 7

Purification of the desired product, TRANS-lactone complex and time-consuming and expensive chromatographic operations.

On the other hand, in the above-described method are formed also by-products of the type balkrishna due to the interaction of other molecules 4β-chloroacetamido-4'-demethylepipodophyllotoxin with already formed by the product of formula 1. In this case, requires the use of excess reactant primary amine of formula 5 to the most comprehensive transformation of parent compounds have minimized the formation of by-products, which requires a complex stage of selection of an excess of amine, which makes this method macoeconomic.

Unexpectedly, the applicant has found that when using the reactant primary amine represented by formula 6, in which a, b and R have the same values as before, but in which the amine functional group is not protected, potential by-products is minimized and their presence does not pose a big obstacle to get a clean end of the connection.

Formula 6

In this case, the direct condensation of 4-chloroacetamido-4'-demethylepipodophyllotoxin formula 4 with the reactant primary amine, without additional stage of protection of the amine functional groups of the past, is happening in terms satisfactory in respect of yield and purity of the obtained product. Thus, in the case of compounds, for which a=3, b=4, c=3, using techniques such as described in WO 2005/100363, conduct synthesis, which includes 11 stages, with a total yield of approximately 15%; synthesis, which is the aim of the present invention, allows to obtain the total yield of 30% only for 3 phase.

Within the targeted synthesis of the present invention used stoichiometric amounts of reactants, which minimizes costs.

Thus, the dominant product of the reaction is an alkylation product comprising a connection to a linear chain by substitution of the primary amine predominant way. Such selective reactivity is unexpected given by-products obtained using the synthesis method described in WO 2005/100363. The use of unprotected amine leads mainly to the desired product.

At the same time, this method presents the advantage of reducing the number of stages, because the protection phase reactant primary amine are no longer necessary.

Thus, the present invention relates to a method of synthesis of compounds of formula 1, comprising the stage of condensation of the intermediate 4β-chloroacetamido-4'-demethylepipodophyllotoxin formula 4 with reagent is m primary amine of formula 6, without prior protection of the amine functional groups.

A preferred manner, the compounds of formula 1 are in the form of hydrochloride.

This condensation reaction proceeds in a direct way, so to amine groups of the used reactant primary amine of formula 6 is not required any protection using a suitable protective group.

In a preferred embodiment, the stage of condensation 4β-chloroacetamido-4'-demethylepipodophyllotoxin formula 4 with reagent unprotected primary amine of formula 6 is carried out in a polar aprotic solvent.

In the preferred embodiment, is used at the stage of condensation of the polar aprotic solvent is chosen from dimethylformamide, dimethylacetamide, N-methylpyrrolidone or more of dimethylsulfoxide.

Also in the preferred embodiment, the condensation reaction is carried out in the temperature interval from -20°C to 30°C. When carrying out process (several tens of grams of observed warming, and therefore preferred to control the reaction temperature. In an even more preferred embodiment, the temperature of the support at 0°C.

The invention relates also to method of synthesis of compounds of formula 1, in which at the stage of condensation of intermediate connected to the I 4β-chloroacetamido-4'-demethylepipodophyllotoxin formula 4 with the reactant primary amine of formula 6 stage should highlight the connection 1.

In a preferred embodiment, the extraction of the compounds of formula 1 is carried out by precipitation in an alcohol solvent such as methanol or ethanol, with subsequent stages of chromatography was carried out with reversed phase in an acidic environment. The connection is cleaned in an acid solution, such as hydrochloric acid. It is not exposed to the risk of epimerization at the stage of lactone, leading to micro derived. Final lyophilization allows you to isolate the salt of the desired connection.

In another preferred embodiment, as a reagent unprotected primary amine of formula 6 using spermine or spermidine to the following formulas 8 and 9.

Formula 8

Formula 9

In the case of condensation with spermidine, unbalanced polyamino will receive 2 isomeric compounds of formula 1 in equal amounts (compounds in which a=3, b=4, R=H and a=4, b=3, R=H).

In the case of condensation with spermine get a connection in which a=3, b=4, and R=(CH2)3-NH2.

In addition, the present invention relates to a method of synthesis of compounds in which a=3, b=4, R=H, namely 2-[3-(4-aminoethylamino)propylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]acetamide", she includes study the condensation 4β-chloroacetamido-4'-demethylepipodophyllotoxin formula 4 with spermidine followed by stage highlight this connection.

In addition, the present invention relates to a method of synthesis of compounds in which a=4, b=3, R=H, namely 2-[4-(3-aminopropylene)butylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]acetamide", she includes stage condensation 4β-chloroacetamido-4'-demethylepipodophyllotoxin formula 4 with spermidine followed by stage highlight this connection.

In addition, the present invention relates to a method of synthesis of compounds in which a=3, b=4, and R=(CH2)3-NH2, namely 2-{3-[4-(3-aminopropylene)butylamino]propylamino}-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]acetamide", she includes a stage of condensation 4β-chloroacetamido-4'-demethylepipodophyllotoxin formula 4 with spermine with the subsequent stage of the selection of this compound.

In addition, the present invention relates to the use of the reagent of the primary amine of formula 6 to obtain the General formula 1 in accordance with the method where they enter the stage of condensation of the reactant primary amine with 4β-chloroacetamido-4'-demethylepipodophyllotoxin formula 4.

The present invention relates also to a method for producing compounds of formula 1 according podofillotoksina formula 2, which includes the following stages and characteristics is : the fact that that used in stage C) the reactant primary amine is a reagent of formula 6. The condensation stage (C) there is a direct way without the stage of protection of the amine functional groups of the used reactant primary amine using any protective group.

a) Obtaining 4'-demethylepipodophyllotoxin formula 3 based on podofillotoksina formula 2.

b) Conversion of 4'-demethylepipodophyllotoxin in the 4β-chloroacetamido-4'-demethylepipodophyllotoxin formula 4.

(C) Condensation 4β-chloroacetamido-4'-demethylepipodophyllotoxin with the reactant primary amine of the formula 6.

Stage a) carry out the preferred way according to the method described in the patent application WO 97/21713, i.e. by processing podofillotoksina a pair of strong acid - aliphatic, aromatic or functionalized sulfide in the presence of an organic or mineral acid, or in the presence of water in the presence or in the absence of organic solvent miscible with water.

Stage b) carry out the preferred manner in accordance with the methodology described in the application WO 2005/100363, i.e. by the reaction of 4'-demethylepipodophyllotoxin obtained at the previous stage, with chloroacetonitrile in an acidic environment.

As the next stage of the selection stage C) is carried out, as previously described, and is used in the reagent of the primary amine contains no protection for their functional amine groups.

If necessary, after the stage of selection of the compounds of General formula 1 can be obtained salt by the action of a mineral or organic acid.

The preferred implementation phase condensation (C) is carried out in a polar aprotic solvent selected from dimethylformamide, dimethylacetamide, N-methylpyrrolidone or more of dimethylsulfoxide.

In another preferred embodiment, the condensation reaction is carried out in the temperature interval from -20°C to 30°C, more preferably at 0°C.

In a preferred embodiment, the extraction of the compounds of formula 1 is carried out by precipitation in an alcohol solvent such as methanol or ethanol, with subsequent phase chromatography was carried out with reversed phase in an acidic environment. The connection is cleaned in an acid solution, such as hydrochloric acid.

In addition, in the preferred embodiment, does not contain protection reactant primary amine of formula 6 used at the stage of condensation (C), is spermine or spermidine.

In the case of use on stage) spermidine get 2 isomeric compounds of formula 1, for which a=3, b=4, R=H and a=4, b=3, R=H in equal proportion.

In the case of condensation with spermine, get a connection, for which a=3, b=4, and R=(CH2)3-NH2.

Izopet the tion also relates to the use of the reagent of the primary amine of formula 6 to obtain the compounds of General formula 1 according podofillotoksina in accordance with the previously described stages (a), then b, then C).

In addition, the present invention relates to a method of synthesis of compounds for which a=3, b=4, R=H, or compounds for which a=4, b=3, R=H, namely 2-[3-(4-aminoethylamino)propylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]ndimethylacetamide, or 2-[4-(3-aminopropylene)butylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]ndimethylacetamide, which includes the following stages.

a) Obtaining 4'-demethylepipodophyllotoxin formula 3 based on podofillotoksina formula 2.

b) Conversion of 4'-demethylepipodophyllotoxin in the 4β-chloroacetamido-4'-demethylepipodophyllotoxin formula 4.

(C) Condensation 4β-chloroacetamido-4'-demethylepipodophyllotoxin formula 4 with spermidine.

These 3 stages stage should allocate 2-[3-(4-aminoethylamino)propylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]ndimethylacetamide, or 2-[4-(3-aminopropylene)butylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]acetamide", she at the same time, if necessary, of the data products have obtained the salt by the action of a mineral or organic acid.

In addition, the present invention relates to a method of synthesis of compounds for which the CSO a=3, b=4 and R=(CH2)3-NH2, namely 2-{3-[4-(3-aminopropylene)butylamino]propylamino}-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]ndimethylacetamide, which includes the following stages.

a) Obtaining 4'-demethylepipodophyllotoxin formula 3 based on podofillotoksina formula 2.

b) Conversion of 4'-demethylepipodophyllotoxin in the 4β-chloroacetamido-4'-demethylepipodophyllotoxin formula 4.

C) Condensation of 4β-chloroacetamido-4'-demethylepipodophyllotoxin formula 4 with spermine

with the subsequent stage of the selection 2-{3-[4-(3-aminopropylene)butylamino]propylamino}-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]ndimethylacetamide and, if necessary, obtain from the salt.

The following examples illustrate the invention without limiting its scope.

Example 1:

The synthesis of the compounds of formula 1 when a=3, b=4, c=3, namely

2-{3-[4-(3-aminopropylene)butylamino]propylamino}-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]ndimethylacetamide in the form of hydrochloride on the basis of 4β-chloroacetamido-4'-demethylepipodophyllotoxin and spermine unprotected amine functional groups

The synthesis scheme is as follows:

To a solution of 1 g (2.1 mmol) 4β-chlorine is atamido-4'-demethylepipodophyllotoxin in 5 ml of DMF was added 0,43 g (2.1 mmol) of spermine formula 8 in 5 ml of DMF. Was stirred for 5 hours Then was added 20 ml of EtOH, then was added a solution of isopropanol/HCl to slightly acidic pH. Fell hydrochloride. The crystals were filtered and dried, obtaining 1.9 g of crude compound 1. Conducted clearing preparative HPLC (Lichrospher 100 RP 18, elution with HCl:c=5 mm). Faction liofilizirovanny, then was extracted with diethyl ether and obtained the hydrochloride of compound 1 amorphous form with a purity of 97%, yield 40%.

T PL 267°C.1H NMR: (DMSO) δ 9,07(d, 1H, J=8,32 Hz, NHCO), of 8.27(s, 1H, ArOH), to 6.80(s, 1H, H5), 6,55(s, 1H, H8), 6,23(s, 2H, H2'H6',), 6,01 (d, 2H, J=12 Hz, OCH20), 5,23(DD, 1H, J=5.3 and 8,1 Hz, H4), to 4.52(d, 1H, J=5,2 Hz, H1), 4,28(t, 1H, J=8 Hz, H11a), of 3.94(DD, 1H, J=8.8 and 10.4 Hz, H11b), and 3.8(m, 2H, CH2CO), 3,63(s, 6H, 2xOCH3), up 3.22(DD, 1H, j=5 and 14.4 Hz, H2), 3,06(m, 3H, H3and CH2NH), 2,99(m, 4H, CH2NH), 2,89(m, 6H, CH2NH), 2,08(t, J=7,6 Hz, 2H, feast upon., CH2), 1,99(q, 2H, J=7,2 Hz, feast upon., CH2), is 1.73(m, 4H, feast upon., CH2)MS-ESI (m/z) 642,2 (MH+); analysis: C33H47N5O8, 4HC1 calculated C% 50,32, H% 6,53, N% 8,89 found C% 50,264, H% to 6.57, N% 8,66.

Example 2

The synthesis of the compounds of formula 1 when a=3, b=4, R=H, namely, the hydrochloride of 2-[3-(4-aminoethylamino)propylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]ndimethylacetamide, and the compounds of formula 1 when a=4, b=3, R=H, namely 2-[4-(3-aminopropylene) butylamino]-N-[9-(4-hydroxy-3,5-dime is oxyphenyl)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]ndimethylacetamide in the form of hydrochloride on the basis of 4β-chloroacetamido-4'-demethylepipodophyllotoxin and spermidine unprotected amine functional groups

The synthesis scheme is as follows:

In the same conditions as in the case of the derivative of example 1, but replacing spermine to spermidine formula 9, are compounds of formula 1 (product a: a=3, b=4, R=H and the product: a=4, b=3, R=H). By analogy with example 1 emit 2 product in an equal ratio with a total yield of 40%.

These products all items are identical to the compounds obtained respectively in examples 31 and 32 in the patent application WO 2005/100363.

The data of examples 1 and 2 can be converted to synthesis of all compounds of formula 1 when using instead of spermine or spermidine appropriate reagent unprotected primary amine of the formula 6.

Example 3

The synthesis of the compounds of formula 1 when a=3, b=4, C=3, namely

2-{3-[4-(3-aminopropylene)butylamino]propylamino}-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro [3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]ndimethylacetamide, in the form of hydrochloride, based on podofillotoksina in stage 3

stage 1

The synthesis scheme is as follows:

10 g (24 mmol) podofillotoksina dissolved in 60 ml triperoxonane acid. Gradually add to 5.4 ml (72 mmol) of methanesulfonate. Stirring is continued for 9 h, the newly added 5.4 ml (72 ml) of dimethyl sulfide and continue stirring for 9 hours, the Content was poured onto ice(600 ml) and extracted with ethyl acetate (3×300 ml). The organic phase is washed with water, then the solution of NaHCO3until neutral. After drying over sodium sulfate, filtration and evaporation obtain 6.3 g of 4'-demethylepipodophyllotoxin, which directly enter into the next stage.

stage 2

To 47,4 ml chloroacetonitrile add 30 g of 4'-demethylepipodophyllotoxin, then with stirring, add 3 drops of concentrated sulfuric acid. Stirred for 3 h at ambient temperature. Then add 300 ml of isopropanol with stirring. The precipitate is filtered and washed with 200 ml of isopropanol. The precipitate is washed with water until neutral, then diethyl ether. After drying in vacuum gain of 34.2 g (yield 96%) solid white (TPL=240°C) corresponding 4β-chloroacetamido-4'-demethylepipodophyllotoxin.

3 stage

On the basis of 4β-chloroacetamido-4'-demethylepipodophyllotoxin obtained at the previous stage, the synthesis continue in accordance with the procedure described in example 1 to obtain a product of formula 1 (a=3, b=4, C=3).

This example can be converted to all compounds of formula 1 when using the appropriate reagents unprotected primary amine of the formula 6.

1. The method of obtaining derivatives of (poly)aminoalkylated of epipodophyllotoxin formula 1 and their farmaceuticas is acceptable salts, in which R represents a hydrogen atom or a group -(CH2)C-NH2when 2≤a, b, C≤5

characterized in that it includes a stage of condensation 4β-chloroacetamido-4'-demethylepipodophyllotoxin formula 4

with the reactant primary amine of formula 6: (a, b, C and R have values similar to the above, and does not include the provisional protection of the amine functional groups
characterized in that the stage of condensation 4β-chloroacetamido-4'-demethylepipodophyllotoxin and reactant primary amine of formula 6 is carried out in a polar aprotic solvent.

2. The method of obtaining derivatives of (poly)aminoalkylated of epipodophyllotoxin formula 1 according to claim 1, characterized in that they receive in the form of hydrochloride.

3. The method according to any one of claims 1 and 2, wherein the polar aprotic solvent is selected from dimethylformamide, dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide.

4. The method according to any one of claims 1 and 2, characterized in that the condensation reaction 4β-chloroacetamido-4'-demethylepipodophyllotoxin and reactant primary amine of formula 6 is followed by a stage of selection of a product of General formula 1.

5. The method according to any one of claims 1 and 2, characterized in that the separation of the product of formula 1 is carried out by OSA is placed in an alcohol solvent followed by chromatography with reversed phase in an acidic environment.

6. The method according to any one of claims 1 and 2, characterized in that the reactant primary amine of formula 6 used at the stage of condensation with 4β-chloroacetamido-4'-demethylepipodophyllotoxin is spermine or spermidine.

7. The method of obtaining the compounds of formula 1 wherein a=3, b=4 and C=3, namely 2-{3-[4-(3-aminopropylene)butylamino]propylamino}-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-
hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]acetamide", she according to any one of claims 1 to 6, characterized in that it includes a stage of condensation 4β-chloroacetamido-4'-demethylepipodophyllotoxin with spermine.

8. The method of obtaining the compounds of formula 1 wherein a=3, b=4, R=H, namely 2-[3-(4-aminoethylamino)propylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]acetamide", she according to any one of claims 1 to 6, characterized in that it includes a stage of condensation 4β-chloroacetamido-4'-demethylepipodophyllotoxin formula 4 with spermidine.

9. The method of obtaining the compounds of formula 1 where a=4, b=3, R=H, namely 2-[4-(3-aminopropylene)butylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]acetamide", she according to any one of claims 1 to 6, characterized in that it includes a stage of condensation 4β-chloroacetamido-4'-demethylepipodophyllotoxin formula 4 with spermidine.

10. The method of obtaining the compounds of formula 1 according to any one of claims 1 and 2, characterized in that it comprises the following stages:
a) obtaining 4'-demethylepipodophyllotoxin formula 3 based on podofillotoksina formula 2


b) conversion of 4'-demethylepipodophyllotoxin formula 3 obtained in stage a), 4β-chloroacetamido-4'-demethylepipodophyllotoxin formula 4
(C) condensation 4β-chloroacetamido-4'-demethylepipodophyllotoxin obtained in stage b)with a reagent of the primary amine of formula 6.

11. The method of obtaining the compounds of formula 1 wherein a=3, b=4 and C=3, namely 2-{3-[4-(3-aminopropylene)butylamino]propylamino}-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]acetamide", she of claim 10, characterized the fact that it comprises the following stages:
a) obtaining 4'-demethylepipodophyllotoxin based on podofillotoksina,
b) conversion of 4'-demethylepipodophyllotoxin obtained in stage a), 4β-chloroacetamido-4'-demethylepipodophyllotoxin,
c) condensation 4β-chloroacetamido-4'-demethylepipodophyllotoxin obtained in stage b), with spermine.

12. The method of obtaining the compounds of formula 1 wherein a=3, b=4 and R=H, namely 2-[3-(4-aminoethylamino)propylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,a-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]acetamide", she according to claim 11, characterized in that it comprises the following stages:
a) obtaining 4'-demethylepipodophyllotoxin based on podofillotoksina,
b) conversion of 4'-demethylepipodophyllotoxin obtained in stage a), 4β-chloroacetamido-4'-demethylepipodophyllotoxin,
c) condensation 4β-chloroacetamido-4'-demethylepipodophyllotoxin obtained in stage b), with spermidine.

13. The method of obtaining the compounds of formula 1 wherein a=3, b=4 and R=H, namely 2-[4-(3-aminopropylene)butylamino]-N-[9-(4-hydroxy-3,5-acid)-8-oxo-5,5A,6,8,8A,9-hexahydrofuro[3',4':6,7]oil[2,3-d][1,3]dioxol-5-yl]acetamide", she of claim 10, characterized in that it includes in the following stages:
a) obtaining 4'-demethylepipodophyllotoxin based on podofillotoksina,
b) conversion of 4'-demethylepipodophyllotoxin obtained in stage a), 4β-chloroacetamido-4'-demethylepipodophyllotoxin,
c) condensation 4β-chloroacetamido-4'-demethylepipodophyllotoxin obtained in stage b), with spermidine.

14. The use of compounds of General formula 6 as defined in claim 1 for producing compounds of General formula 1 according to claims 1-6.

15. The use of compounds of General formula 6 to obtain the compounds of General formula 1 in accordance with the methods for p-13.

 
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