Connection camptothecin, methods for their preparation, intermediate compounds and therapeutic compositions

 

(57) Abstract:

Describes new compounds camptothecin General formula I or II in racemic form, in the form of enantiomers or any combination of these forms, where R1denotes lower alkyl, lower halogenated and lower alkoxylate alkyl, R2, R3, R4represent independently H, halogen, lower halogenated, lower alkyl, (CH2)mNR6R7, (CH2)mOR6(CH2)n[N = X], substituted or unsubstituted, where the Deputy is a lower alkyl, or R2and R3together form metalinox or ethylenoxide, R5denotes H, halogen, lower alkyl, lower alkoxy, (CH2)mNR6R7or (CH2)n[N = X], substituted or unsubstituted, where the Deputy represents lower alkyl, R6and R7represent independently H or lower alkyl, aryl lower alkyl, halogen lower alkyl, R9denotes lower alkyl, arylalkyl, R16denotes H or or21; R17indicates OR6, R18and R19represent independently H, halogen, lower alkyl, lower alkoxy or hydroxy; R20denotes H or halogen; R21represents H, lower alkyl, CHO, the disappearance, X denotes the required circuit for picking heterocyclic group and selected from the group consisting of O, S, CH2CH, NH, NR9; or its pharmaceutically acceptable salt. Describes how to obtain new compounds, intermediate compounds and therapeutic pharmaceutical composition. The compounds find use as inhibitors of topoisomerase and anticancer agents. 6 C. and 19 C.p. f-crystals, 2 PL.

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Camptothecin is a natural compound that has been allocated for the first time from the leaves and bark of the Chinese plant called Camptotheca acuminata (Cm. Wall et al., J. Amer. Chem. Soc. 88: 3888 (1966)). Camptothecin represents Pyh connection consisting of a fragment of indolizino[1,2-b] quinoline, condensed with 6-chain - hydroxyacetone. The carbon in position 20, which is - hydroxy, is asymmetric and reports the torque capacity of the molecule. Natural form of camptothecin has an absolute configuration of S relative to carbon 20 and corresponds to the following formula:

< / BR>
Camptothecin has antiproliferative activity in certain lines of cancer cells, including cell lines, tumors of the colon, lung and breast the proliferative activity of camptothecin related to its inhibitory activity against topoisomerase I DNA.

It was shown that hydroxylation was absolutely necessary for the activity of camptothecin as in vivo, in vitro (Camptothecins: New Anticancer Agents, Putmesil, M. et al, ed., p.27 (CRC Press. 1995); Wall, M. et al. Cancer Res. 55: 753 (1995); Hertzberg et al., J. Med. Chem., 32:715 (1982) and Crow et al. , J. Med. Chem., 35:160 (1992)). This invention relates to a new class derived camptothecin, in which hydroxylation replaces natural - hydroxylation of camptothecin. Compounds according to this invention show strong biological activity, which is unexpected relative to the previous level of knowledge.

Thus, an object of the present invention are new compounds camptothecin, which differ from all known compounds camptothecin the fact that they contain - hydroxylation (or open hydroxycarboxylic form) instead of hydroxyacetone (or open hydroxycarboxylic form); or their pharmaceutically acceptable salts. Under connection camptothecin understand the connection with the same structural skeleton that camptothecin (i.e., a fragment of indolizino[1,2-b]quinoline, which is condensed with 6-chain - hydroxyacetone) with other chemical substitutions or without other chemical substitutions on this skeletal structure (Nadine below. Under - hydroxyacetone understand lactone, which consists of additional carbon atom between the carbon carboxyl and the carbon bearing the hydroxy-group - hydroxylation. - hydroxylation of the seven "closed" or "open" circuit in which the ester bond between the carbonyl group and the adjacent oxygen atom obtained, which is manifested by the formation of carboxylic acid and hydroxyl groups, which may or may not be substituted.

Connection camptothecin according to this invention may then include the replacement fragment of indolizino[1,2-b]quinoline (for example, to improve the solubility of the compound) or in open or closed - hydroxyacetone (for example, to improve stability of the connection). Examples of substitutions on a closed - hydroxyacetone include alkyl substitution (e.g. ethyl) - on - carbon. Examples of substitution in the open - hydroxyacetone include alkyl substitution on the carbon substitution (for example, the amidation) of the formed carboxylic acid and substitution (e.g., esterification) or a protective group formed by hydroxyl groups.

More specifically, an object of the present invention are the compounds of formula I igde

R1denotes lower alkyl, lower alkenyl, lower quinil, lower halogenated and lower alkoxy-lower alkyl or lower alkylthio-lower alkyl;

R2, R3, R4represent independently H, halogen, lower halogenated, lower alkyl, lower alkenyl, cyano, lower cianelli, nitro, lower nitroalkyl, amido, lower aminoalkyl, hydrazino, lower hydrazinolysis, azido, lower azidoethyl, (CH2)mNR6R7, (CH2mOR6, (CHmSR6, (CH2)mCO2R6, (CH2)mNR6C(O)R8, (CH2)mC(O)R8, (CH2)mOC(O)R8, O(CH2)mNR6R7, OC(O)NR6R7, OC(O)(CH2)mCO2R6or (CH2)n[N=X], OC(O)[N=X], (CH2)mOC(O)[N=X] (where [N=X] in this invention denotes a heterocyclic group of 4-7 circuits with the nitrogen atom N, which is a member of the heterocyclic group, and X denotes received the members necessary for completing a heterocyclic group selected from the group consisting of O, S, CH2CH, N, NR9and COR10), aryl or lower arylalkyl, substituted (i.e. substituted 1-4 times a heterocyclic or aryl group) or unsubstituted, where Vice is oxyalkyl, lower alkoxy or lower alkoxy-lower alkyl), or R2and R3together form a chain of 3 or 4 links, and the elements of this chain selected from the group consisting of CH, CH2, O, S, N or NR9;

R5denotes H, halogen, lower halogenated, lower alkyl, lower alkoxy, lower alkoxy-lower alkyl, lower alkylthio-lower alkyl, cycloalkyl, lower cycloalkenyl, cyano, cianelli, lower alkyl-lower sulfonylated, lower hydroxyalkyl, nitro, (CH2)mC(O)R8, (CH2)mNR6C(O)R8, (CH2)mNR6R7, (CH2)mN(CH3)(CH2)nNR6R7, (CH2)mOC(O)R8, (CH2)mOC(O)NR6R7,

(CH2)mS(O)qR11, (CH2)mP(O)R12R13, (CH2)2P(S)R12R13or (CH2)n[N-X] , OC(O)[N=X], (CH2)mOC(O) [N=X], aryl or substituted lower arylalkyl (i.e., 1-4 times on the aryl group or heteroaryl) or unsubstituted, where the Deputy is a lower alkyl, halogen, nitro, amino, lower alkylamino, lower halogenated, lower hydroxyalkyl, lower alkoxy or lower alkoxy-lower alkyl;

R6and R7represent independently H is tlaltelolco, lower alkenyl, lower alkoxy-lower alkyl, lower halogenated or aryl or substituted lower arylalkyl (i.e., 1-4 times on the aryl group) or unsubstituted, where the Deputy is a lower alkyl, halogen, nitro, amino, lower alkylamino, lower halogenated, lower hydroxyalkyl, lower alkoxy or lower alkoxy-lower alkyl;

R8represents H, lower alkyl, lower hydroxyalkyl, amino, lower alkylamino, lower alkyl-lower aminoalkyl, lower aminoalkyl, cycloalkyl, lower cycloalkenyl, lower alkenyl, lower alkoxy, lower alkoxy-lower alkyl, lower halogenated or aryl or substituted lower arylalkyl (i.e., 1-4 times on the aryl group) or unsubstituted, where the Deputy is a lower alkyl, halogen, nitro, amino, lower alkylamino, lower halogenated, lower hydroxyalkyl, lower alkoxy or lower alkoxy-lower alkyl;

R9represents H, lower alkyl, lower halogenated, aryl or aryl substituted by one or more groups selected from radicals of lower alkyl, halogen, nitro, amino, lower alkylamino, lower halogenated, lower hydroxyalkyl, lower alkoxy or lower alkoxy-lower alkyl;

R10represents H, lower Alky or more groups, selected from radicals of lower alkyl, lower halogenated, lower hydroxyalkyl or lower alkoxy-lower alkyl;

R11denotes lower alkyl, aryl, (CH2)mOR14, (CH2)mSR14, (CH2)2NR14R15or (CH2)m[N-X];

R12and R13denote independently lower alkyl, aryl, lower alkoxy, aryloxy or amino;

R14and R15represent independently H or lower alkyl, or aryl;

R16denotes H or or21;

R17indicates OR6or NR6R7;

R18and R19represent independently H, halogen, lower alkyl, lower alkoxy or hydroxy;

R20denotes H or halogen;

R21represents H, lower alkyl, CHO, or C(O) (CH2)mCH3;

m is an integer between 0 and 6;

n is 1 or 2; and

q denotes an integer from 0 to 2; and [N=X] denotes a heterocyclic group with 4-7 links, X denotes the required circuit for picking heterocyclic group and selected from the group consisting of O, S, CH2CH, N, NR9and COR9; or a pharmaceutically acceptable salt of the latter.

In particular this invention relates to compounds of formula I and formula II, S-lower alkyl or lower alkylthio-lower alkyl; R5denotes H, halogen, lower halogenated, lower alkyl, lower alkoxy, lower alkoxy-lower alkyl, lower alkylthio-lower alkyl, cycloalkyl, lower cycloalkenyl, cyano, cianelli, lower hydroxyalkyl, nitro, (CH2)mC(O)R8, (CH2)mNR6C(O)R8, (CH2)mNR6R7, (CH2)mN(CH3)(CH2)nNR6R7, (CH2)mOC(O)R8, (CH2)mOC(O)NR7R7or (CH2)n[N= X], OC(O)[N=X], (CH2)mOC[N=X], aryl or lower arylalkyl, substituted or unsubstituted; R12and R13denote independently lower alkyl; R16indicates OR21and R18, R19and R20denote h

More specifically, this invention relates to compounds of formula I and formula II, as described above, in which R1denotes lower alkyl, lower alkenyl, lower halogenated or lower alkoxy-lower alkyl; R2, R3and R4represent independently H, halogen, lower halogenated, lower alkyl, nitro, amido, lower aminoalkyl, hydrazino, lower hydrazinolysis, azido, lower azidoethyl, (CH2)mNR6R7, (CH2)mOR6, (CH2)mSR6, (CH2and R3together form a chain of 3 or 4 links, and these circuit elements selected from the group consisting of CH, CH2, O, S, N or NR9; R5denotes H, halogen, lower halogenated, lower alkyl, lower alkoxy, lower alkoxy-lower alkyl, lower alkylthio-lower alkyl, lower hydroxyalkyl, nitro, (CH2)mC(O)R8, (CH2)mNR6C(O)R8, (CH2)mNR6R7, (CH2)mN(CH3) (CH2)nNR6R7, (CH2)mOC(O)R8, (CH2)mOC(O)NR6R7or (CH2)n[N= X] , OC(O)[N= X] , substituted or unsubstituted, or (CH2)mOC[N=X]; R6and R7represent independently H, lower alkyl, lower hydroxyalkyl, lower alkyl-lower aminoalkyl, lower aminoalkyl, cycloalkyl, lower cycloalkenyl, lower alkoxy-lower alkyl, aryl, lower arylalkyl or lower halogenated; R8represents H, lower alkyl, lower hydroxyalkyl, lower alkylamino, lower alkyl-lower aminoalkyl, lower aminoalkyl, cycloalkyl, lower cycloalkenyl, lower alkenyl, lower alkoxy, lower alkoxy-lower alkyl, lower halogenated, aryl or lower arylalkyl; R9represents H, lower al is 1 denotes lower alkyl; and R14and R15represent independently H or lower alkyl.

More specifically, the preferred compounds of this invention are the compounds of formula I above in which R1denotes an ethyl group; R2and R3represent independently H, lower alkyl, halogen, lower halogenated or (CH2)mOR6or R2and R3together form methylenedioxy or Ethylenedioxy and R4and R5represent independently H, lower alkyl, (CH2)mNR6R7or (CH2)n[N= X] , unsubstituted or substituted lower alkyl. Preferably, R4represents H or (CH2)mNR6R7where R6and R7represent independently H or lower alkyl, a R5denotes H or lower alkyl or (CH2)n[N=X], unsubstituted or substituted lower alkyl; as an example [N=X], substituted or unsubstituted, you can lead the radicals piperidyl, morpholinyl, piperazinil, imidazolyl and 4-methylpiperazine.

More preferably, R2denotes H or halogen and preferably H, chlorine or fluorine; and R3represents H, lower alkyl, halogen or or6where R6the seat is B>2and R3form together methylendioxy or Ethylenedioxy.

More specifically, this invention has as its primary purpose the products described in the examples below, in particular the products corresponding to the following formula:

--5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4': 6,7] -indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--5,12-diethyl-4,5-dihydro-5-hydroxy-1H-oxepin(3',4': 6,7]- indolizino[1,2-b]quinoline-3,15-(4H,13H)-dione

--8-ethyl-2,3,8,9-tetrahydro-8-hydroxy-10H,12H-[1,4]-like[2,3-g] oxepin[3',4': 6,7]-indolizino[1,2-b]-quinoline-10,13-(15H)-dione

--10-benzyloxy-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3',4': 6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--5-ethyl-4,5-dihydro-5,10-dihydroxy-1H-oxepin-[3', 4': 6,7]- indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--11-(dimethylamino)methyl-5-ethyl-4,5-dihydro-5,10-dihydroxy-1H-oxepin[3',4': 6,7] -indolizino[1,2-b] quinoline-3,15(4H,13H)-dione

--5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepin[3', 4': 6,7]-indolizino[1,2-b]quinoline-3,15-(4H,13H)-dione

--9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepin[3',4':6,7] -indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--5-ethyl-9,10-debtor-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4': 6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--7-ethyl-7,8-dihydro-7-hydroxy-N,11N-[1,3]dioxolo[4,5-g]oxep': 6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepin[3', 4': 6,7]- indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--9,11-dichloro-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4':6,7]- indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepin[3', 4':6,7]- indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4': 6,7] -indolizino[1,2-b] quinoline-3,15(4H,13H)-dione

--10-chloro-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4': 6,7] -indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--10-chloro-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4': 6,7] -indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--5,12-diethyl-4,5-dihydro-5,10-dihydroxy-11-morpholinomethyl-1H-oxepin[3',4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--5,12-diethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepin[3', 4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--5-ethyl-4,5-dihydro-5-hydroxy-12-methyl-1H-oxepin[3',4':6,7]- indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4 - methylpiperazine)-1H-oxepin[3', 4':6,7]-indolizino- [1,2-b]quinoline-3,15(4H,13H)-dione

--9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-morpholinomethyl - 1H-oxepin[3',4':6,7]-indolizino[1,2-b] quinoline-3,15(4H,13H)-dione

--5-ethyl-4,5-dihydro-5-hydroxy-12-(4-methyl-pipermail-1H-oxepin[3', 4': 6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--5-ethyl-4,5-dihydro-5-hydroxy-12-morpholinomethyl-1H - oxepin[3', 4': 6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperazine)- 1H-oxepin[3',4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-12-morpholinomethyl-1H-oxepin[3',4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

--5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12- (4-methylpiperazine)-1H-oxepin[3',4':6,7]-indolizino[1,2-b] quinoline-3,15(4H,13H)-dione

--5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-morpholinomethyl-1H - oxepin[3',4':6,7]-indolizino[1,2-b] quinoline-3,15(4H,13H)-dione

--5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-piperidinomethyl-1H-oxepin[3',4':6,7]-indolizino[1,2-b] quinoline-3,15(4H,13H)-dione

--8-ethyl-2,3,8,9-tetrahydro-8-hydroxy-16-(4-methylpiperazine)- 10H, N-(1,4)like(2,3-g)-oxepin[3', 4': 6,7] indolizino[1,2-b] quinoline-10,13[15H]-dione

--9-chloro-5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-12-morpholinomethyl-1H - oxepin[3',4':6,7]-indolizino[1,2-b] quinoline-3,15(4H,13H)-dione

or their pharmaceutically acceptable salts.

This invention more specifically provides compounds of formula II, described above, where R1denotes an ethyl group; R2and R3>and R3together form methylenedioxy or Ethylenedioxy and R4and R5represent independently H, lower alkyl, (CH2)mNR6R7or (CH2)n[N=X], unsubstituted or substituted lower alkyl; R20denotes H and R17indicates OR6where R6denotes H or lower alkyl, or NR6R7where R6and R7independently represent H, lower alkyl, aryl or lower arylalkyl. Preferably, R4represents H or (CH2)mNR6R7where R6and R7represent independently H or lower alkyl; R5denotes H or lower alkyl or (CH2)n[N=X], unsubstituted or substituted lower alkyl; and R17indicates OR6where R6denotes H or lower alkyl, or their pharmaceutically acceptable salts. As an example [N=X] you can lead a radical piperidyl, morpholinyl, piperazinil, imidazolyl and 4-methylpiperazine.

Even more preferably, R2denotes H or halogen and preferably H, chlorine or fluorine; and R3represents H, lower alkyl, halogen or or6where R6represents H, lower alkyl or lower arylalkyl, and, preferably, H, fluorine, chlorine, methyl or methoxy. Prepective invention offers products, described later in the examples, in particular, the products corresponding to the following formula:

--tert-butyl --ethyl--hydroxy-- (8-hydroxymethyl-9-oxo- (11H)-indolizino-[1,2-b]quinoline-7-yl)-propionate

--ethyl --ethyl--hydroxy-- (8-hydroxymethyl-9-oxo(11H)- indolizino-[1,2-b]quinoline-7-yl)-propionate

--ethyl--hydroxy-- (8-hydroxymethyl-9-oxo(11N)-indolizino-[1,2-b]quinoline-7-yl) -propionic acid

--methyl --ethyl--hydroxy-- (8-hydroxymethyl-9-oxo(11N)-indolizino-[1,2-b]quinoline-7-yl) -propionate

--ethyl --ethyl-,-debtor--hydroxy-- (8-hydroxymethyl-9-oxo(11N)-indolizino-[1,2-b]quinoline-7-yl) -propionate

--ethyl --ethyl--hydroxy-- (8-hydroxymethyl-9-oxo(11N)- indolizino-[1,2-b]quinoline-7-yl)-propionate

--tert-butyl --ethyl--hydroxy-- (8-hydroxymethyl-9-oxo(11H)-indolizino-[1,2-b] quinoline-7-yl)-propionate

(12-ethyl-8-hydroxymethyl-9-oxo(11N)- indolizino-[1,2-b]quinoline-7-yl)-propionic acid

-- (12-benzyloxy-8-hydroxymethyl-9-oxo(11N)-indolizino-[1,2-b] quinoline-7-yl) --ethyl-- hydroxy-propionic acid (E)

or their pharmaceutically acceptable salt.

In the application here, the term lower in relation to the alkyl, alkylthio and alkoxygroup denotes a saturated aliphatic hydrocarbon group, linear or branched, soderzhatelya, methoxy, ethoxy. In relation to alkenyl or quinil, the term denotes the lower group containing 2-6 carbon atoms and one or more double or triple links, examples of which include vinyl, allyl, isoprenyl, pentenyl, hexenyl, propenyl, ethinyl, PROPYNYL and butynyl. The term cycloalkyl means a cycle containing 3-7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term aryl denotes a hydrocarbon compound, a mono-, di - or tricyclic, at least one aromatic cycle, and each cycle contains a maximum of 7 units, as, for example, phenyl, naphthyl, antracol, biphenyl or indenyl. The term halogen denotes chlorine, bromine, iodine and fluorine. Radicals, corresponding to the lowest halogenated, lower zainoulline, lower nitroalkyl, lower aminoalkyl, lower hydrazinolysis, lower azidoethyl, lower arylalkyl, lower hydroxyalkyl, lower alkoxy-lower alkyl, lower alkylthio-lower alkyl and lower alkylsulfonyl-lower alkyl are substituted respectively with one to three substituents, such as halogen, cyano, nitro, amido, hydrazino, azido, aryl, hydroxy, lower alkoxy, lower alkylthio or lower sulfonyl. Lower alkyl is B>, NH(CH3)2or N(CH3)(CH2CH3). Examples [N= X] include piperidinyloxy, morpholinyl, piperazinilnom and imidazolidinyl group.

As observed for camptothecin, the carbon atom carrying the hydroxyl group, - hydroxyacetone, or hydroxycarboxylic group of compounds of the present invention, is asymmetric. Therefore, compounds according to this invention have two possible enantiomeric configuration, i.e. the configuration of "R" and "S". The invention includes these two enantiomeric configuration and any combination of these configurations, as well as RS-racemic mixture. In the interest of simplicity, when in structural formulas do not specify any particular configuration, it should be understood that presents two enantiomeric configuration, and mixtures thereof.

The aim of the present invention are also methods of obtaining compounds of General formula I and General formula II or of camptothecin or substituted camptothecin, or by chemical synthesis.

This invention relates therefore to a method for producing compounds of formulas I and II, based on the substituted camptothecin, namely, that:

-- hydroxylation and R20have the above significance, with a receiving - hydroxyestra General formula A

< / BR>
where R1, R2, R3, R4, R5and R20have the above significance. Formed in thus connecting A bond of carbon-carbon adjacent to the carbinol tear a suitable oxidant thus, to obtain the compound of formula B

< / BR>
where R1, R2, R3, R4, R5and R20have the above significance. It then processes the functional alkylating agent and the formyl group of the compounds of formula B are cut with getting - hydroxyether General formula C

< / BR>
where R1, R2, R3, R4, R5, R18and R20have the above significance and R17indicates OR6and R6denotes lower alkyl, cycloalkyl, lower cycloalkenyl, lower alkenyl, lower alkoxy-lower alkyl or aryl or lower arylalkyl;

-- join the General formula C cyclist obtaining hydroxylating compounds of General formula D

< / BR>
where R1, R2, R3, R4, R5, R18, R19and R20have the above meaning,

--lactone of General formula D reveal with getting connected to the above value; R16indicates OR21where R21denotes H or lower alkyl; and R17indicates OR6or other6and R6represents H, lower alkyl, cycloalkyl, lower cycloalkyl, lower cycloalkenyl, lower alkenyl, lower alkoxy-lower alkyl or aryl or lower arylalkyl.

Some compounds of formula E can be also obtained by hydrolysis of ester bonds of the corresponding compounds of formula C. compounds of General formula E in which R16and/or R17denote independently a hydroxy-group, can be tarifitsirovana or lidirovali under classical conditions, known to specialists in this area, with the production of esters or amides corresponding to formula E.

In the above-described method, the group R1, R2, R3and R4can be protected, if necessary, according to the classical methods of protection (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley and Sons 1981)). During this procedure, there is a restoration of a reducing agent in a suitable solvent, for example, sodium borohydride in methanol. Stage corresponds to the formation of compound B from compound A, perform under oxidative conditions, for example, leads to compounds, which lead period kisankhazana alkylating agent can be performed using the derived metal for example, lithium or zinc, or with the use of ether carboxylic acid in an anhydrous aprotic solvent such as tetrahydrofuran. Stage lactonization compound D obtained from compound C, usually carried out under acidic conditions, for example, processing triperoxonane acid or gaseous hydrogen chloride dissolved in anhydrous solvent such as dichloromethane or dioxane. Trip lactoovo cycle connection D to obtain compound E can be performed, for example, by hydrolysis under alkaline conditions followed by neutralization.

Examples of the substituted camptothecin used as starting materials, can be found in US Patents Nos. 4473692, 4604463, 4894956, 5162532, 5395939, 5315007, 5264579, 5258516, 5254690, 5212317 and 5341745, PCT Patent Application Nos. US 91/08028, US94/06451, US90/05172, US92/04611, US93/10987, US91/09598, EP94/03058 and European Patent Applications Nos. 325247, 495432, 321122 and 540099.

This invention relates also to a method for producing compounds of formulas I and II, namely, that:

connection with the General formula M

< / BR>
where R1, R18and R19have the above significance, and R20denotes a hydrogen atom or halogen, associated with the 2-halogen-3-kinalimutan General formula N

< / BR>
where R2, R3, R O

< / BR>
where R1, R2, R3, R4, R5, R18, R19and R20and X have the above meaning;

- then compound of General formula O cyclist with obtaining the compounds of formula D as described above.

In the above-described method, the group R1, R2, R3and R4can be protected, if required, in accordance with the classical methods of protection (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley and Sons 1981)). The formation of compound O from compounds of the General formulas M and N carry out treatment, known to specialists in this area, called the reaction Mitsunobu (Mitsunobu, O. et al. Syntheses. P. 1 (1981)). It consists in replacing the hydroxyl group of the compound N-nucleophile, such as the connection M, or deprotonirovannym derivative of the latter, the processing of a phosphine, such as triphenylphosphine, and azodicarboxylate derived, for example diethyl-in primary forms, in an aprotic solvent such as, for example, tetrahydrofuran or N,N-dimethylformamide. The cyclization of compounds O carried out preferably in the presence of a palladium catalyst (such as palladium diacetate) in alkaline conditions (provided, for example, alkali metal acetate, possibly combined with agent-fatal or N,N-dimethylformamide, at a temperature of between 50oC and 120oC (R. Grigg et al. Tetrahedron 46, page 4003 (1990)). Compounds of General formula M are new. They can be obtained according to the method lies in the fact that

-- carbonyl pyridine of General formula

< / BR>
where R1and R20have the above significance and R22denotes a halogen atom or lower alkoxy, protect acetamino group, to obtain compounds of formula F

< / BR>
where R1, R20and R22have the above meaning and Z and Z' groups independently represent lower alkyl or together form a saturated hydrocarbon chain with 2 to 4 carbon atoms:

-- hydroxymethylene group is introduced into the compound of formula F with obtaining compounds of General formula G

< / BR>
where R1, R20, R22Z and Z' have the above meaning,

-- then the alcohol group of the compounds of General formula G protects obtaining compounds of General formula H

< / BR>
where R1, R20, R22Z and Z' have the above significance and R23denotes a protective group, an alcohol group.

--acetal compounds of General formula H is released from the protective group to obtain compounds of General formula I'

< / BR>
where R1, R20, R22jirousek agent with obtaining - the hydroxyether General formula J

< / BR>
where R1, R20, R22and R23have the above meaning, R18and R19have the meanings indicated in the General formula II, and R17indicates OR6and R6denotes lower alkyl, cycloalkyl, lower cycloalkenyl, lower alkenyl, lower alkoxy-lower alkyl or aryl or lower arylalkyl,

--protective group, R23otscheplaut from compounds of General formula J with obtaining compounds of General formula K

< / BR>
where R1, R18, R19, R20and R22have the above significance and R17indicates OR6where R6denotes lower alkyl, cycloalkyl, lower cycloalkenyl, lower alkenyl, lower alkoxy-lower alkyl or aryl or lower arylalkyl,

--join the General formula K cyclist with obtaining the compounds of formula L

< / BR>
where R1, R18, R19, R20and R22have the above significance, and, finally,

--the radical R22connection L is converted into a carbonyl obtaining compounds of General formula M

< / BR>
where R1, R18, R19and R20have the above significance. Carbonyl group of 4-acyl-2-pyridine (obtained, for example, according Lamattina, J. L. J. He is accordance with the classical conditions well-known experts in this field (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley and Sons 1981)). When R22is chlorine or fluorine, thus obtained intermediate product is treated with a sodium alcoholate or potassium alcoholate in an aprotic solvent (e.g. acetonitrile), or in alcohol, from which was obtained the alcoholate at a temperature between 0oC and 100oC obtaining the compounds of formula F. the Latter may be processed to attach lithium in position 3 abilities or alkyllithium (for example, musicalities) in solvent - simple ether, such as tetrahydrofuran, at temperatures between -100oC and 0oC. To the thus obtained litoranea intermediate connection type formulirui electrophile such as N,N-dimethylformamide, and the resulting aldehyde, after hydrolysis, is treated with a reducing agent such as sodium borohydride, to obtain the compounds of General formula G. the Protection of the alcohol group of compound G is carried out according to classical conditions, known to specialists in this field, to obtain the compounds of General formula H. Examples of protective groups of the alcohol are such groups, which form ethers (for example, methyl, methoxymethyl, t esters (for example, formate, acetate and isobutyrate). Examples of other protective groups are primary hydroxyl described in Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley and Sons 1981). Removing the protective groups of compounds of General formula H, resulting in the compound of General formula I' perform in the selective environment, allowing to preserve the integrity of the radical R23for example, by treatment in acidic conditions (for example, triperoxonane acid). Election terms of protection and removal to protect functional groups known to experts in the art (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley and Sons 1981)). Treatment of compound I' functionalized alkylating agent with obtaining - hydroxyether General formula J can be performed using enolate lithium or zinc-derived ether carboxylic acid in an aprotic anhydrous solvent, for example tetrahydrofuran. The protective group R23compounds of General formula J otscheplaut obtaining compounds of General formula K under the conditions of removal of the protective groups known to the experts in this field. For example, when R23is a benzyl group, an alcohol solution of the compounds of General formula J back at the palladium catalyst in a hydrogen atmosphere with a pressure of 0.5-himer, processing triperoxonane acid or gaseous hydrogen chloride dissolved in anhydrous solvent such as dichloromethane or dioxane) to give the - hydroxyacetanilide cycle with seven links, such as in the compound of General formula L. the Compounds of General formula L can be converted into pyridone General formula M, for example, by treatment with hot hydrochloric acid or trimethylsilylimidazole.

2-Halogen-3-kinalimutan General formula N can be obtained from acetanilide General formula P

< / BR>
where R2, R3and R4have the meanings specified for compounds of formulas I and II. In the following procedures R2, R3and R4can be protected according to the classical methods of protection (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley and Sons 1981)).

Then can be obtained the compounds of formula N according to the following procedure: anilines of the formula P N-acetimidoyl processing azetiliruet agent such as, for example, acetic anhydride. Thus obtained acetanilide treated at a temperature between 50oC and 100oC, preferably 75oC, a reagent known to specialists in this area under the name of the reagent of Vilsmeier (obtained by the action phosphorilation-3-hinolincarbonova (see, for example, Meth-Cohn et al. J. Chem. Soc., Perkin Trans I p. 1520 (1981); Meth-Cohn et al. J. Chem. Soc., Perkin Trans I p.2509 (1981); and Nakasimhan et al. J. Am. Chem. Soc., 112. P. 4431 (1990)). Chlorine in position 2 of 2-chloro-3-hyalinobatrachium may be substituted by iodine or bromine by heating the product in an inert solvent, such as acetonitrile, in the presence of salt iodine or bromine (e.g. sodium iodide or tetrabutylammonium). Traces of acid, such as concentrated hydrochloric acid, may be necessary to catalyze this transformation. 2-Halogen-3-hinolincarbonova easily reduced to the 2-halogen-3-kinalimutan corresponding to the General formula N, in classical terms, known to specialists in this field, such as treatment in an alcohol solvent (e.g. methanol) sodium borohydride at a temperature between 0oC and 40oC.

The compounds of formula N can be obtained according to the following procedure: anilines of General formula P, described above, acelerou reaction with a nitrile (such as chloroacetonitrile or propionitrile) in the presence of trichloride boron and other Lewis acid, such as trichloride aluminum, titanium tetrachloride or chloride diethylamine, in an aprotic solvent or mixture of aprotic solvent, with patiwat ethylmaleimide in an aprotic solvent, such as acetonitrile, in the presence of a base, such as triethylamine, then treated with an alkaline alcoholate, for example sodium methylate in methanol, to obtain ethyl-2-hydroxy-3-chinainternational, substituted in position 4. The last connection is converted into ethyl-2-chloro-3-chinainternational treatment phosphorylchloride. When in position 4 of the quinoline is chloromethylene group, nucleophilic substitution can be performed by treatment with a secondary amine such as dimethylamine, N-methylpiperazine, morpholine or piperidine. Then ethyl-2-chloro-3 - chinainternational restore diisobutylaluminium in an aprotic solvent such as dichloromethane, to obtain 2-chloro-3-kinalimutan General formula N. Analogues intermediate (N) compounds have been described in the literature and, in particular, in PCT Application 95/05427.

This invention relates to new industrial products, which are intermediate products for producing products of formulas I and II, which are the products of formulas I' and M, as described above.

Some compounds of this invention can be obtained in the form of pharmaceutically acceptable salts according to conventional methods. Acceptable salts include sebaie as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluensulfonate, pamoate, salicylate, oxalate, and stearate. Salts formed with bases such as sodium hydroxide or potassium, are also included in the scope of the present invention, when applicable. Relative to other examples of pharmaceutically acceptable salts are watching "Pharmaceutical Salts", J. Pjarm. Sci., 66:1 (1977).

The compounds of this invention have interesting pharmacological properties, namely the compounds of this invention affect the activity of topoisomerase I and/or II and antitumor activity. This method assumes that the compounds of this invention possess anti-parasitic and/or antiviral activity. Thus, the compounds of this invention can be used for various therapeutic purposes.

Compounds of the invention can inhibit topoisomerase, for example, type I and/or II, in a patient, for example, a mammal, such as man, in the introduction of this to the patient an effective therapeutic amount of the compounds of formula (I) or formula (II).

The compounds of this invention also possess antitumor activity. They can be used to treat the tumor is about the amount of compounds of formula (I) or formula (II). Some examples of tumors or carcinomas include cancers of the esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, breast, cervical, endometrial, ovarian, prostate, testicular, bladder, kidney, liver, pancreas, bones, connective tissue, skin, eyes, brain and Central nervous system, and thyroid cancer, leukemia, Hodgkin's disease, lymphomas other than Hodgkin's disease, multiple melanoma and other

They can also be used to treat parasitic infections by inhibiting blood flagellate parasites (for example, when infections of trypanosomes or Leishmania) or by inhibition of Plasmodium (e.g., malaria), but also for the treatment of viral infections or diseases.

These properties make the compounds of formula I and formula II suitable for pharmaceutical use. The object of this application are also the compounds of formula I and II, described above, as well as additive salts with pharmaceutically acceptable organic or mineral acids these compounds of formulas I and II, as medicines and pharmaceutical compositions containing as acttack way to pharmaceutical compositions containing an effective amount of the compounds according to this invention or its additive salt with a pharmaceutically acceptable acid, together with a pharmaceutically acceptable carrier according to the chosen route of administration (e.g. oral, intravenous, intraperitoneal, intramuscular, transdermal or subcutaneous). The pharmaceutical composition (e.g., therapeutic) may be in the form of solids, liquids, liposomes or lipid micelles.

The pharmaceutical composition may be in the form of solids, for example, powders, pills, granules, tablets, liposomes, capsules or suppositories. The pill, tablet or capsule can be coated with a substance capable of protecting the composition from the effects of stomach acid or enzymes in the stomach of a subject during a sufficient period of time for passing the composition in undigested in the small intestine. Thus, the connection may be entered locally, for example, location near the tumor. The connection may also be introduced by way of prolonged release (for example, in the form of a composition with a slow release or via infusion pump). Below is chose, dextrin, amidon, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and wax. A pharmaceutical composition comprising a compound of this invention may be represented also in the form of a liquid, such as solutions, emulsions, suspensions or forms of slow release. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, such as polyethylene glycol, and their mixtures, in various proportions, in water.

The object of this invention is also the use of compounds of formulas I and II described above, for obtaining a medicinal product intended for the inhibition of topoisomerase and, more specifically, topoisomerase type I and II, of a medicinal product intended for the treatment of tumors, a medicinal product intended for the treatment of parasitic infections, as well as pharmaceuticals for the treatment of viral infections or diseases.

The dose of a compound according to this invention, provided for the treatment of diseases or disorders mentioned above, vary depending on the method of administration, the age is or your veterinarian. This dose is called here "therapeutically effective amount".

In the following experimental section, you can find an illustration of the pharmacological properties of these compounds.

In that case, if all technical and scientific terms used herein not otherwise defined, they shall have the meaning understood at the present time the average expert in the field to which this invention. All publications, patent applications, all patents and all other mentioned here sources of information incorporated herein by reference.

The following examples are presented to illustrate the methods described above and in any case should not be construed as limiting the invention.

EXPERIMENTAL SECTION

Example 1: tert-butyl --ethyl--hydroxy-- (8-hydroxymethyl-9-oxo(11N)-indolizino [1,2-b] quinoline-7-yl)-propionate 1. A. 4-ethyl-3,4-dihydroxy-1H-pyrano [3',4':6,7] indolizino[1,2-b]quinoline-14(4H,M)-he

Sodium borohydride (14 g, 370 mmol) is added in portions to a suspension of (S)-(+)-camptothecin (14 g, 40 mmol), which can be obtained from various commercial sources such as Aldrich Chemical Co. (Milwaukee, WI), in methanol (750 ml) and the resulting mixture was ran at ambient temperature. Then the solvent is evaporated under reduced pressure, the residue is extracted into water (250 ml), neutralized by adding acetic acid (21 ml) and left to stand for 2 hours at 4oC. the resulting suspension is filtered and washed successively with cold water, acetone and diethyl ether, which, after drying under reduced pressure, allows to obtain the target compound in the form of a white solid substance, so pl. 280oC.

1.b. 8-formyloxyethyl-7-propionylcarnitine[1,2-b]quinoline-9(11N)-he

The solution metaperiodate sodium (14 g, 65 mmol) in water (140 ml) is added dropwise to a suspension of 4-ethyl-3,4-dihydroxy-1H - pyrano[3',4':6,7]indolizino[1,2-b]quinoline-14(4H,M)-she (13,4 g, 38 mmol) in glacial acetic acid (720 ml) and the resulting solution was stirred for 1 hour at ambient temperature. Then the reaction mixture was poured into a mixture of ice/water (650 ml) and the resulting suspension is stirred for 1/2 hour, then filtered and washed successively with water, isopropyl alcohol and diethyl ether and alcohol, which, after drying under reduced pressure to give the target compound (11.5 g) in the form of a pale yellow solid, so pl. > 200oC (decomp.).

1. C. tert-butyl-ethyl-hydroc shivambu magnetic stirrer in anhydrous diethyl ether (50 ml) in an argon atmosphere, activate by adding dropwise chlorotrimethylsilane (0.75 ml, 5.7 mmol) and again stirred for 15 minutes at ambient temperature to heating under reflux. Then the heating bath is removed and added dropwise tert-butylbromide (15 ml, 100 mmol) at speeds that guarantee the maintenance of reflux distilled. External heating restore and continue to heat again for 1 hour. The ether solution formed from the reagent reformed, leave to cool to ambient temperature, then transferred via cannula to a suspension of 8-formyloxyethyl-7-propionylcarnitine[1,2-b] quinoline-9(11N)-she (1.6 g, 4.7 mmol) in anhydrous tetrahydrofuran (40 ml) in an argon atmosphere. The reaction mixture was stirred at reflux for 1 hour, then allowed to cool to ambient temperature and the reaction stopped by the addition of saturated solution of ammonium chloride (100 ml) and extracted with chloroform (3 x 100 ml). The combined chloroform extracts are dried on sodium sulfate, evaporated and the residue purified by gel-chromatography on silica gel (1-2% MeOH/CH2Cl2), which allows to obtain 0.64 g of target compound (31%) in the form of a pale yellow solid, 1H), 5,10 (s, 2H), 5,24 (s, 2H), 7,40 (s, 1H), to 7.59 (t, 1H), 7,83 (t, 1H), of 7.90 (d, 1H), to 8.20 (d, 1H), 8.34 per (s, 1H).

13C-NMR (CDCl3): 8,18; 27,90; 34,59; 45,34; 49,91; 58,55; 77,39; 82,42; 100,52; 127,67; 127,97; 128,10; 128,64; 129,44; 129,79; 130,42; 130,99; 142,86; 148,69; 152,75; 155,16; 162,38; 172,24.

IR (KBr): 764; 1016; 1157; 1580; 1651; 1726.

Example 2: ethyl --ethyl--hydroxy-- (8-hydroxymethyl-9-oxo(11N)- indolizino[1,2-b]quinoline-7-yl)-propionate

A suspension of zinc (500 mg, of 7.64 mmol) and 8-formyloxyethyl-7-propionylcarnitine [1,2-b] quinoline-9(11H)-she (400 mg, 1.15 mmol) in anhydrous tetrahydrofuran (20 ml) containing 10 mg of hydroquinone are heated under reflux in an argon atmosphere. The heating bath is removed and initiate the exothermic reaction by adding drops of ethylbromoacetate and a small crystal of iodine. The reflux support the addition dropwise of ethylbromoacetate (500 μl, 4,48 mmol), then the reaction mixture is again heated under reflux for 1 hour. After cooling to ambient temperature the reaction is stopped by adding a saturated solution of ammonium chloride (10 ml) and methanol (30 ml). The resulting mixture was dissolved in dichloromethane (30 ml), washed with water and dried on sodium sulfate. Then remove the solvent and carry out the purification column is solid, so pl. 157-161oC.

1H-NMR (CDCl3): of 0.93 (t, 3H), of 1.20 (t, 3H), 2,02 (m, 2H), of 3.07 (DD, 2H), 4,11 (K, 2N), 4,9 (CE, 1H), to 5.08 (s, 2H), 5,23 (s, 2H), 7,45 (s, 1H), 7.62mm (t, 1H), 7,80 (t, 1H), of 7.90 (d, 1H), they were 8.22 (d, 1H), at 8.36 (s, 1H).

13C-NMR (CDCl3): 8,09; 14,01; 34,67; 44,85; 49,94; 58,31; 61,09; 77,21; 100,78; 127,78; 127,96; 128,11; 128,72; 129,16; 129,65; 130,60; 131,32; 142,76; 152,55; 155,09; 162,22; 172,59.

IR (KBr): 766; 1009; 1184; 1582; 1647; 1750.

Example 3: 5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3',4':6,7]-indolizino [1,2-b]quinoline-3,15(4H,13H)-dione

tert-Butyl --ethyl--hydroxy-- (8-hydroxymethyl-9-oxo(11H)-indolizino[1,2-b] quinoline-7-yl)-propionate (1.45 g, of 3.32 mmol) dissolved in anhydrous dichloromethane (25 ml) and treated with a saturated solution of ammonium chloride in diformate (100 ml). The resulting mixture was support at -20oC for 16 hours. The precipitate is filtered, washed with methanol and dried under reduced pressure, giving 662 mg (55%) of target compound in the form of a yellow solid, so pl. > 300oC.

1H-NMR (DMSO): of 0.90 (t, 3H), 1,20 (K, 2N), with 3.27 (DD, 2H), from 5.29 (s, 2H), 5,49 (DD, 2H), 7,42 (s, 1H), 7,73 (t, 1H), of 7.90 (t, 1H), 8,16 (t, 2H), 8,71 (s, 1H).

13C-NMR (DMSO): 8,45; 36,48; 42,54; 50,68; 61,44; 73,34; 99,78; 122,71; 127,83; 128,15; 128,75; 129,08; 130,07; 130,61; 131,81; 144,66; 148,04; 152,80; 155,91; 159,26; 172,08.

IR(KBr): 761; 1127; 1204; 1285; 1580; 1653; 1757.

Example 4:- is p potassium hydroxide (0.1 N., 30 ml) are added to 5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin-[3', 4': 6,7]-indolizino [1,2-b]quinoline-3,15(4H, 13H)-dione (500 mg, 1.38 mmol) and the resulting suspension is stirred for 16 hours, resulting in the formation of almost clear liquid that is filtered. The filtrate is acidified to pH 3.5 1 N. hydrochloric acid and the yellow precipitate is removed by filtration, washed with water and acetone, then dried under reduced pressure. Get 415 mg (79%) of target compound in the form of a monohydrate, so pl. 165-167oC.

1H-NMR (DMSO): of 0.82 (t, 3H), 2,10 (m, 2H), and 2.83 (d, 2H), 3,12 (d, 2H), 3,25 (CE, 1H), to 4.81 (s, 2H), 5,26 (s, 2H), 5,76 (CE, 1H), 7,38 (s, 1H), 7,71 (t, 1H), to 7.84 (t, 1H), 8,10 (d, 1H), 8,18 (d, 1H), a 8.34 (s, 1H), 12,15 (CE, 1H).

13C-NMR (DMSO): 8,16; 34,80; 46,71; 50,36; 55,73; 76,53; 100,17; 127,50; 128,00; 128,26; 128,69; 129,06; 130,01; 130,45; 131,63; 142,57; 148,09; 153,19; 156,07; 161,22; 172,27.

IR(KBr): 1020; 1188; 1413; 1586; 1651; 1694.

Example 5:

methyl --ethyl--hydroxy-- (8-hydroxymethyl-9-oxo(11H)- indolizino[1,2-b]quinoline-7-yl)-propionate

5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4':6,7]-indolizino [1,2-b] quinoline-3,15(4H, 13H)-dione (180 mg, 0.5 mmol) in suspensions of methanol (50 ml) is treated with 6 N. dried hydrogen chloride in methanol (0.5 ml) and heated under reflux until complete dissolution (4 hours). Volatile components viplavam solution (15 ml). The organic fraction is dried on sodium sulfate and evaporated. The remaining solid is purified column chromatography on silica gel (3% MeOH/CH2Cl2and the product is distilled and extracted in diethyl ether, filtered and dried, giving 120 mg (58%) of target compound in the form of a pale yellow solid, so pl. 163-166oC.

1H-NMR (CDCl3): of 0.93 (t, 3H), 2,2 (m, 2H), 3,05 (DD, 2H), 3,49 (s, 3H), 3,62 (s, 3H), is 4.93 (s, 2H), 5,22 (d, 2H), 5,52 (d, 2H), 7,21 (s, 1H), 7.62mm (t, 1H), 7,81 (t, 1H), to $ 7.91 (d, 1H), they were 8.22 (d, 1H), at 8.36 (s, 1H).

13C-NMR (CDCl3): 7,74; 35,54; 46,82; 50,15; 51,67; 58,10; 65,33; 78,03; 100,17; 125,57; 127,70; 128,04; 128,10; 128,35; 129,53; 130,39; 130,94; 143,87; 148,75; 152,94; 157,83; 161,74; 171,35.

IR (KBr): 1207; 1595; 2655; 1709.

Example 6 ethyl-ethyl -,-debtor--hydroxy-- (8-hydroxymethyl-9-oxo(11H)-indolizino[1,2-b]quinoline-7-yl)-propionate

Approximately 1/2 of the total number of ethylbromoacetate (1.8 ml, 14 mmol), 8-formyloxyethyl-7-propylaniline[1,2-b]quinoline-9(11N)-he (2.0 g, of 5.75 mmol), obtained as in Example 1.b., in suspensions with anhydrous THF (10 ml) is added dropwise in an argon atmosphere to a suspension of zinc (1,25 g, and 17.2 mmol) in anhydrous THF at reflux (40 ml), then add the remaining ethylbromoacetate. The reaction mixture supports the environment of the reaction stopped by the addition of saturated aqueous solution of ammonium chloride (20 ml) and the reaction mixture was extracted with dichloromethane (3 x 20 ml). The combined organic extracts are dried and concentrated. The residue is extracted in diethyl ether (10 ml), filtered and purified column chromatography (SiO2CH2Cl2/MeOH 98/2) to obtain 664 mg (26%) of target compound in the form of a yellow solid, so pl. 208-209oC.

1H-NMR (CDCl3): of 0.91 (t, 3H), of 1.38 (t, 3H), 2,32 (m, 2H), 4,8 (CE, 1H), to 4.38 (K, 2N), 5,09 (d, 2H), 5,13 (DD, 2H), 7,42 (s, 1H), 7,55 (t, 1H), 7,72 (t, 1H), 7,79 (d, 1H), 8,08 (d, 1H), they were 8.22 (s, 1H).

13C-NMR (CDCl3): 6,97; 13,93; 28,63; 50,18; 56,27; 63,15; 77,20; 81,96(t); 101,27; 116,40(t); 127,67; 127,77; 127,97; 128,31; 129,26; 130,33; 130,94; 131,23; 143,16; 148,34; 150,20; 151,91; 161,21; 163,21 (t)

IR(KBr): 1124; 1308; 1591; 1647; 1748.

Example 7 ethyl --ethyl--hydroxy-- (8-hydroxymethyl-9-oxo(11H)-indolizino [1,2-b]quinoline-7-yl)-propionate

A suspension of zinc (1,25 g of 19.1 mmol) and 8-methyl-7-propionylcarnitine[1,2-b]quinoline-9-(11H)-she (500 mg, of 1.43 mmol), such as obtained Kingsbury, W. D., Tetrahedron Lett. 29:6847 (1988), and silver acetate (250 mg, 1.50 mmol) in anhydrous tetrahydrofuran (10 ml) was stirred at ambient temperature in an argon atmosphere. At the end of 10 minutes, the reaction mixture was activated by adding dropwise molar solution chloroethylamine (10 ml, 10 mmol), then add ethylbromoacetate (1.25 ml, 11.3 mmol) dropwise and the resulting mixture estabishing solution of tartrate of potassium and sodium (10 ml). The resulting mixture was again stirred for 1 hour, filtered and concentrated under reduced pressure. The residue is extracted into dichloromethane (30 ml), washed with water, dried, concentrated and purified column chromatography (SiO2CH2Cl2/MeOH 98/2) to give 93 mg (15%) of the desired product in the form of a pale yellow solid, so pl. 185-188oC.

1H-NMR (CDCl3): of 0.91 (t, 3H), of 1.17 (t, 3H), of 1.99 (m, 2H), 2.49 USD (s, 3H), 3,10 (DD, 2H), 4,11 (K, 2N), 4,6 (CE, 1H), 5.25 in (s, 2H), 7,65 (t, 1H), to 7.67 (s, 1H), 7,80 (t, 1H), of 7.90 (d, 1H), they were 8.22 (d, 1H), 8.34 per (s, 1H).

13C-NMR (CDCl3): 8,02; 13,99; 14,72; 33,14; 43,97; 50,02; 61,0; 76,54; 101,90; 127,65; 127,84; 128,08; 128,81; 128,88; 130,74; 131,59; 131,65; 140,33; 147,64; 152,96; 153,61; 162,11; 172,91.

IR(KBr): 762; 1192; 1576; 1653; 1740.

Example 8: tert-butyl --ethyl--hydroxy-- (8-hydroxymethyl-9-oxo-(11H)-indolizino[1,2-b] quinoline-7-yl)-propionate

Acetic anhydride (70 μl, 0.7 mmol) is added dropwise to a solution of tert-butyl --ethyl--hydroxy-- (8-hydroxymethyl-9-oxo(11H)-indolizino [1,2-b] quinoline-7-yl)-propionate (200 mg, 0.46 mmol) and triethylamine (140 μl, 1 mmol) in dichloromethane (5 ml) and the resulting mixture stirred at ambient temperature for 21 hours. Volatile components are evaporated and the residue purified column chromatography on silica gel (1-2% MeOH/CHSS="ptx2">

1H-NMR (CDCl3): to 0.88 (t, 3H), 1,32 (s, N), of 1.93 (m, 2H), 2,07 (s, 3H), of 2.97 (DD, 2H), 4,8 (CE, 1H), 5,28 (s, 2H), 5,59 (DD, 2H), 7,39 (s, 1H), 7,63 (t, 1H), 7,80 (t, 1H), of 7.90 (d, 1H), 8,23 (d, 1H), 8.34 per (s, 1H).

13C-NMR (CDCl3): 8,02; 21,06; 27,91; 35,05; 45,58; 50,16; 77,52; 82,26; 100,59; 124,59; 124,21; 127,91; 128,10; 128,14; 128,97; 129,18; 130,68; 131,46; 142,85; 148,29; 152,43; 158,49; 161,83; 171,13; 171,90.

Example 9: 5,12-diethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3',4':6,7]-indolizino [1,2-b]quinoline-3,15(4H,13H)-dione

This compound is produced by way similar to example 1 except that in stage 1.A. instead of camptothecin use 7-ethyl-camptothecin (Sawada et al., Chem. Pharm. Bull. 39:2574 (1991)). The target compound is obtained in the form of a bright yellow solid, so pl. > 270oC.

1H-NMR (DMSO): to 0.92 (t, 3H), of 1.39 (t, 3H), 1.93 and (K, 2N), is 3.08 (d, 2H), 3,25 (K, 2N), 3,51 (d, 2H), 5,32 (s, 2H), 5,52 (DD, 2H), 7,42 (s, 1H), 7,76 (t, 1H), 7,89 (t, 1H), 8,18 (d, 1H), 8,32 (d, 1H).

13C-NMR (DMSO): 8,46; 14,15; 22,42; 36,50; 42,54; 49,95; 61,45; 73,35; 99,68; 122,61; 124,27; 126,76; 127,70; 128,27; 129,27; 129,92; 130,18; 145,17; 145,82; 148,57; 152,15; 155,89; 159,26; 172,08.

Example 10: --ethyl-- (12-ethyl-8-hydroxymethyl-9-oxo(11H)-indolizino[1,2-b]quinoline-7-yl) - hydroxypropionic acid

This compound is produced by way similar to example 4, except that 5,12-diethyl-4,5-dihydro-5-hydroxy-1H - oxepin[3',4':6,7]-indolizino[1 the in-3,15(4H, 13H)-dione.

It is obtained in the form of solids slightly non-standard white, so pl. 238-239oC.

1H-NMR (DMSO): of 0.82 (t, 3H), of 1.35 (t, 3H), a 2.01 (m, 2H), 2,85 (d, 2H), 3,18 (d, 2H), 3,22 (K, 2N), to 4.81 (s, 2H), 5,00 (CE, 1H), 5,24 (s, 2H), 5,78 (CE, 1H), 7,38 (s, 1H), to 7.77 (t, 1H), 7,86 (t, 1H), 8,18 (d, 1H), 8,28 (d, 1H), 12,10 (CE, 1H).

13C-NMR (DMSO): 8,12; 14,15; 22,41; 34,78; 46,74; 49,65; 55,71; 76,51; 100,04; 124,22; 126,63; 127,48; 128,12; 128,21; 129,94; 130,02; 143,10; 148,69; 152,62; 156,03; 161,22; 172,22.

Example 11: 8-ethyl-2,3,8,9-tetrahydro-8-hydroxi-10H-[1,4] like[2,3-g] oxepin[3',4':6,7]-indolizino[1,2-b]quinoline-10,13(15 NM)-dione

11.a. 2-ethyl-2-(2-methoxy-4-pyridyl)-1,3-dioxolan

Water distil azeotrope during the night with the use of the apparatus of the Dean-Stark from a mixture of 2-chloro-4-propionylcarnitine (10 g, 59 mmol) (obtained as in Lamattina. J. L. J. Heterocyclic Chem. 20, p.553 (1983)), of ethylene glycol and p-toluenesulfonic acid (250 mg) in toluene (150 ml). Then the solvent is removed under reduced pressure, the acid is neutralized with saturated aqueous bicarbonate (100 ml) and the product extracted with ether. The combined ether extracts are washed with salt solution, dried on sodium sulfate and evaporated, giving 13.3 g (96%) of the crude product, protected carbonyl group, which is heated under reflux with 3 equivalent
, tert-butyl-metaloxide/hexane (TVMA/NC) 50/50). Then the solution in acetonitrile, filtered and evaporated. The residue is extracted into ether, washed with water and saline solution, dried on sodium sulfate and evaporated to obtain a brown oil which is distilled (70-75oC 0,04 mbar); 10.7 g (total yield 81%) of product (F) is extracted in the form of a transparent liquid.

11.B. 2-ethyl-2-(3-hydroxymethyl-2-methoxy-4-pyridyl)-1,3-dioxolane (G)

Tert-utility (1.7 M in pentane, 100 ml, 170 mmol) is added dropwise via cannula to a solution of bromoethylene (13 ml, 85 mmol) in anhydrous tetrahydrofuran (300 ml) at -78oC in argon atmosphere. The obtained white precipitate was stirred at -78oC for 1 hour, then add 2-ethyl-2-(2-methoxy-4-pyridyl)-1,3-dioxolane (10 g, with 44.8 mmol) and the reaction mixture is stirred for 15 minutes at -78oC, for 1 hour at 0oC and for 1 hour at ambient temperature. After cooling to -78oC add anhydrous N,N-dimethylformamide (100 mmol) and the reaction mixture is left to warm to ambient temperature, then stirred for 16 hours, followed by analysis by thin-layer chromatography (SiO2TWO/NC 50/50), for podtverzhde the reaction mixture was extracted with diethyl ether (200 ml, 50 ml, 50 ml). The combined extracts are dried on sodium sulfate and evaporated to obtain a yellow oil, which was purified column chromatography (SiO2TWO/NC: 0/100 - 5/95 to elution derived mesitylene, then 20/80 - 50/50 for elution of the product) to give the intermediate aldehyde (7 g). The aldehyde was dissolved in methanol (100 ml) and treated with sodium borohydride (5 g, 132 mmol) and the resulting mixture is stirred until complete consumption of the intermediate aldehyde (about 1 hour) according to the analytical determination using thin-layer chromatography. Then the solvent is evaporated, the residue extracted into ether, washed with water and brine and the solvent is evaporated. Column chromatography (SiO2TWO/NC 10/90 - 50/50) of the residue gives 7 g (total yield 62%) of product (G) in the form of a yellow oil.

11.with. 2-(3-benzoyloxymethyl-2-methoxy-4-pyridyl)-2-ethyl-1,3 - dioxolan (H)

A solution of 2-ethyl-2-(3-hydroxymethyl-2-methoxy-4-pyridyl)-1,3 - dioxolane (7 g, 30 mmol) and benzylchloride (5 ml, 45 mmol) in anhydrous tetrahydrofuran (150 ml) is added dropwise to a suspension of sodium hydride (80% in mineral oil, 1.85 g, 61 mmol) in anhydrous tetrahydrofuran (100 ml) and the reaction mixture heated under reflux for 16 hours. For the (50 ml) and the reaction mixture is concentrated under reduced pressure. The residue is dissolved in diethyl ether (150 ml) and washed with water and brine, dried and evaporated. Purification of column chromatography (SiO2TWO/NC; 5/95 -20/80) gives the product is protected by benzyl (H), 9 g (87%) in the form of a clear oil.

11.d. 1-(3-benzoyloxymethyl-2-methoxy-4-pyridyl)-propane-1-he (I')

2-(3-benzoyloxymethyl-2-methoxy-4-pyridyl)-2-ethyl-1,3-dioxolane (9 g, 27 mmol) is treated triperoxonane acid (10 ml) and water (5 ml) in a bath with a temperature of 120oC for 3 hours. The reaction mixture was concentrated under reduced pressure and the remaining traces of acid neutralized by adding saturated aqueous sodium bicarbonate. Extraction with ether and subsequent column chromatography (SiO2TWO/NC; 10/90) leads to obtain 5.5 g (70%) of product (I).

11. e. tert-butyl --ethyl--hydroxy-- (3-benzoyloxymethyl-2-methoxy-4-pyridyl) propionate

Tert-butylbromide (13 ml, 80 mmol) is added dropwise to a suspension of zinc (5,3 g, 80 mmol, activated processing 6 N. HCl for 10 seconds, followed by washing with water to neutral pH, acetone and diethyl ether) in anhydrous tetrahydrofuran (60 ml) at reflux. Reaction medium support when negreansenior-2-methoxy-4-pyridyl)-propane-1-she (5.8 g, 20 mmol) in anhydrous tetrahydrofuran (20 ml) and the reaction mixture was stirred at reflux for 1 hour. The reaction is stopped at 0oC saturated aqueous ammonium chloride (100 ml) and the reaction mixture extracted with diethyl ether. The combined extracts are dried on sodium sulfate and evaporated to obtain a yellow oil, which was purified column chromatography (SiO2TWO/NC; 5/95 - 10/90) to give tert-butyl ether (J) (7 g, 95%) in the form of a clear oil.

11. f. tert-butyl --ethyl--hydroxy-- (3-hydroxymethyl-2-methoxy-4-pyridyl)-propionate

Tert-butyl --ethyl--hydroxy-- (3-benzoyloxymethyl-2-methoxy-4-pyridyl)propionate (1 g, 2.5 mmol)hydrogenolysis at atmospheric pressure and at ambient temperature using 5% palladium on charcoal as catalyst (50 mg) and absolute ethanol as solvent (10 ml). Once the reaction is finished (6 hours), the catalyst is separated by filtration and the solvent is evaporated to obtain 0.7 g (90%) of product (K) of sufficient purity for subsequent use in the synthesis.

11. g. 5-ethyl-1,5-dihydro-5-hydroxy-9-methoxyacridine [3,4-c]pyridine-3-(4H)-he (L)

Tert-butyl --ethyl--hydromachine 3 hours at ambient temperature. Volatile components are evaporated and the residue purified column chromatography (SiO2CH2Cl2/MeOH; 100/0 - 98/2) to give a clear oil, which after treatment with toluene gives 5.9 g of product (L) (89%) in the form of white crystals, so pl. 97oC.

11. h. 5-ethyl-1,5-dihydro-5-hydroxy-oxepin[3,4-c] pyridine-3,9(4H, 8H)-dione (M)

1 N. hydrochloric acid (20 ml), 5-ethyl-1,5-dihydro-5-hydroxy-9-methoxyacridine[3,4-C]pyridine-3(4H)-he (0.5 g, 2.1 mmol) is heated under reflux for 9 hours. The reaction mixture was concentrated under pressure and the residue is again dried by addition and evaporation of toluene, twice, then left overnight under reduced pressure in the presence of phosphorus pentoxide. The oil obtained is dissolved in anhydrous acetonitrile (5 ml) and stirred in an argon atmosphere for 24 hours. The precipitate is filtered off and dried to obtain 0,23 g (49%) of a white solid substance (M), so pl. 118-119oC.

11.i. 6,7-Ethylenedioxy-2-iodine-3-kinalimutan (N)

Use the methods described Meth-Cohn et al., J. Chem. Soc. Perkin Trans. I, p.1520 (1981); Meth-Cohn et al., J. Chem. Soc. Perkin Trans. I, p. 2509 (1981) and Nakasimhan et al., J. Am. Chem. Soc., 112, p.4431 (1990). Add 3,4-etilendioksitiofenom (22 g, 113 ml) of reagent Vilsmeier obtained by adding kaplama ice water for 0.5 hour in an argon atmosphere. The resulting mixture was heated to 75oC for 16 hours. After cooling to ambient temperature the reaction mixture was added to a mixture of ice water (300 ml) and extracted with dichloromethane (5 x 200 ml). The combined organic extracts are dried on sodium sulfate, filtered and concentrated. The solid residue is placed in suspension in dichloromethane (20 ml), filtered and dried under reduced pressure to obtain 10 g (35%) of 2-chloro-6,7-ethylenedioxythiophene-3-carbaldehyde in the form of a yellow solid, so pl. 222-224oC. This intermediate compound is treated with sodium iodide (30 g, 0.2 mol) and concentrated hydrochloric acid (1.5 ml) in acetonitrile at reflux (150 ml) for 24 hours. After cooling to ambient temperature the solvent is removed under reduced pressure and the residue extracted in 50% aqueous tetrahydrofuran (200 ml), filtered, washed with tetrahydrofuran and dried under reduced pressure to obtain 12 g of 6,7-dioxyethylene-2-eothinon-3-carbaldehyde in the form of a yellow solid, so pl. 155-157oC. This intermediate compound is treated with sodium borohydride (2 g, 52 mmol) in methanol (200 ml) at ambient temperature for 0.5 the solid is dried under reduced pressure in the presence of phosphorus pentoxide to obtain 11 g of (6,7-Ethylenedioxy-2-eothinon-3-yl)-methanol in the form of a yellow solid, so pl. 178-180oC.

11. j. 5-ethyl-8-(6,7-dioxyethylene-2-iodine-3-rhinoliner)-1,5 - dihydro-5-hydroxyhexane[3,4-c]pyridine-3,9(4H,8H)-dione (ABOUT)

For 5 minutes diethylazodicarboxylate (570 μl, 3.6 mmol) is added dropwise to a solution of 5-ethyl-1,5-dihydro-5 - hydroxyhexane[3,4-c]pyridine-3,9(4H, 8H)-dione (400 mg, to 1.79 mmol), the compound obtained in the previous stage 11. i. (770 mg, of 2.23 mmol), and triphenylphosphine (934 mg, 3.58 mmol) in a mixture of anhydrous THF/DMSO (about 8/1./about., 45 ml) and the reaction mixture is stirred in an argon atmosphere at ambient temperature for 16 hours. Then the reaction mixture was concentrated under reduced pressure and the residue is dissolved in chloroform (100 ml). The resulting solution was washed with brine (4 x 50 ml), dried on sodium sulfate and evaporated. The residue is purified column chromatography (SiO2CH2Cl/MeOH; 99/1-98/2) to give 650 mg (66%) of product (A) in the form of a white solid substance, so pl. 165-167oC.

11. k. 8-ethyl-2,3,8,9-tetrahydro-8-hydroxy-10H, N-[1,4] like [2,3-g]oxepin[3',4':6,7]indolizino[1,2-b]quinoline-10,13-(15 NM)-dione

5-ethyl-8-(6,7-Ethylenedioxy-2-eothinon-3-yl)methyl-4,5-dihydro-5 - hydroxy-(1H,3H)oxepin[3,4-c]pyridine-3-dione (600 mg, 1.1 mmol), tetrabutylammonium (352 mg, 1.1 mmol), azeta the Ute 90oC in argon atmosphere for 16 hours. After cooling to ambient temperature the white precipitate was separated from the reddish solution. This precipitate is filtered off and dried under reduced pressure. The crude product is suspended in water, filtered and dried under reduced pressure at phosphorus pentoxide to obtain 250 mg of the target compound in the form of a clear yellow solid, so pl. > 250oC.

1H-NMR(DMSO): of 0.91 (t, 3H), of 1.87 (m, 2H), is 3.08 (d, 1H), 3,51 (d, 1H), of 4.45 (s, 2H), 5,19 (s, 2H), vs. 5.47 (DD, 2H), 6,02 (CE, 1H), 7,33 (s, 1H), 7,54 (s, 1H), 7,55 (s, 1H), 8,43 (s, 1H).

13C-NMR (DMSO): 8,43; 36,47; 42,54; 50,52; 61,43; 64,43; 73,31; 99,07; 112,27; 113,14; 122,00; 124,24; 128,18; 129,74; 144,59; 145,01; 145,33; 147,63; 150,88; 155,88; 159,23; 172,07.

Example 12: 10-benzyloxy-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4':6,7]- indolizino[1,2-b]quinoline-3,15-(4H,13H)-dione

12.a. (6-benzyloxy-2-iodine-3-quinoline) methanol

This connection will get in the manner similar to that described in stage 11. i. example 11, but using 4-benzyloxyaniline instead of 3,4-etilendioksitiofenom. Purification of column chromatography on silica gel, using dichloromethane as the eluent required for selection (8%) sufficiently pure intermediate 6-benzyloxy-2-chlorine results (6-benzyloxy-2-eothinon-3-yl)-methanol, so pl. 147-149oC.

12. b. 8-(6-benzyloxy-2-iodine-3-rhinoliner)-1,5 - dihydroxy-5-ethyl-5-hydroxyhexane[3,4-c]pyridine-3,9(4H,8H)-dione

This connection receive according to the method described in stage 11.j. example 11, but using (6-benzyloxy-2-eothinon-3-yl)methanol instead of (6,7-Ethylenedioxy-2-eothinon-3-yl) methanol. The compound is obtained in the form of a white solid substance, so pl. 197-199oC.

12.with. 10-benzyloxy-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3',4':6,7] - indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

This connection get in the way similar to that specified in stage 11. k. example 11, but using 8-(6-benzyloxy-2-iodine-3-rhinoliner)-1,5-dihydroxy-5-ethyl-5-hydroxyhexane [3,4-c] pyridine-3,9(4H, 8H)-dione instead of 5-ethyl-8-(6,7-Ethylenedioxy-2-eothinon - 3-yl)methyl-4,5-dihydro-5-hydroxy-(1H,3H)oxepin [3,4-c]pyridine-3-dione. The target compound is formed in the form of a clear yellow solid, so pl. > 250oC.

1H-NMR (DMSO): of 0.90 (t, 3H), of 1.85 (m, 2H), is 3.08 (d, 1H), 3,50 (d, 1H), 5.25 in (s, 2H), and 5.30 (s, 2H), 5,50 (DD, 2H), equal to 6.05 (s, 1H), 7,30-of 7.70 (m, 8H), 8,10 (d, 1H), 8,55 (s, 1H).

13C-NMR (DMSO): 8,43; 36,48; 38,28; 50,65; 61,42; 70,00; 73,32; 99,05; 107,71; 122,05; 123,42; 128,18; 128,26; 128,70; 129,40; 130,19; 130,48; 130,63; 136,65; 144,18; 144,90; 150,53; 155,91; 157,31; 159,24; 172,06.


This compound is produced by way similar to that described in example 4, but using 10-benzyloxy-5-ethyl-4,5-dihydro-5 - hydroxy-1H-oxepin[3', 4': 6,7] indolizino[1,2-b] quinoline-3,15(4H,13H)-dione instead of 5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4': 6,7] indolizino [1,2-b]quinoline-3,15(4H, 13H)-dione. It is obtained in the form of a yellow solid, so pl. 171-173oC.

1H-NMR (DMSO): to 0.80 (t, 3H), 2,00 (m, 2H), 2,85 (d, 1H), 3.15 in (d, 1H), 4,80 (s, 2H), 5.25 in (s, 2H), and 5.30 (s, 2H), 5,75 (CE, 1H), 7,30 (s, 1H), 7,35-of 7.70 (m, 7H),8,10 (d, 1H), 8,55(s, 1H).

13C-NMR (DMSO): 8,11; 34,75; 46,68; 50,35; 55,70; 69,97; 76,51; 99,45; 107,78; 123,28; 127,64; 128,18 (2C); 128,26; 128,70 (2C); 129,33; 130,17; 130,47; 130,57; 136,69; 142,79; 144,17; 150,93; 156,03; 157,19; 161,20.

Example 14: 5-ethyl-4,5-dihydro-5,10-dihydroxy-1H-oxepin[3',4':6,7]-indolizino [1,2-b]quinoline-3,15-(4H,13H)-dione

10-benzyloxy-5-ethyl-4,5-dihydro-5-hydroxy-1H - oxepin[3',4':6,7]-indolizino[1,2-b] quinoline-3,15-(4H, 13H)-dione (370 mg, of 0.79 mmol) is treated with hydrogen at atmospheric pressure and at ambient temperature using 10% palladium on charcoal as catalyst (60 mg) and triperoxonane acid as solvent (15 ml). Upon completion of the reaction (16 hours) to the reaction mixture was added dichloromethane (50 ml) and methanol (50 ml), the catalyst is filtered off and the volatile*, containing traces triperoxonane acid. These traces are removed co-distillation with 1,4-dioxane. The product is obtained in the form of an orange solid substance, so pl. 150oC (decomp.), with a purity sufficient for further use in the synthesis.

1H-NMR (DMSO): to 0.89 (t,3H), 1.85 to (K, 2N), to 3.02 (d, 1H), 3.45 points (d, 1H), 5,19 (s, 2H), lower than the 5.37 (d, 1H), 5,50 (d, 1H), 5,98 (CE, 1H), 7,26 (s, 1H), 7,31 (s, 1H), 7,40 (d, 1H), 8,00 (d, 1H), 8,42 (s, 1H), 10,32 (s, 1H).

1C-NMR (DMSO): 8,47; 36,50; 42,61; 50,57; 61,46; 73,35; 98,84; 109,02; 121,83; 123,18; 129,50; 129,85; 130,12; 130,80; 143,39; 145,10; 149,69; 155,97; 159,30; 172,11.

Example 15: 11-(dimethylamino)methyl - 5-ethyl-4,5-dihydro-5,10-dihydroxy-1H - oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dio

15. a. 11-(dimethylamino)-5-ethyl-4,5-dihydro-5,10 - dihydroxy-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

A suspension of 10-benzyloxy-5-ethyl - 4,5-dihydro-5-hydroxy-1H-oxepin[3', 4': 6,7]-indolizino[1,2-b]quinoline-3,15-(4H,13H)-dione (260 mg, 0.69 mmol) in acetic acid (15 ml) is treated with 37% aqueous formaldehyde (500 μl) and 40% aqueous dimethylamine (500 μl) and the resulting mixture stirred at ambient temperature for 16 hours. The reaction mixture is concentrated to dryness and the residue purified column chromatography (SiO2CH2Cl2/MeOH; 100/0 - 90/10) followed the ylamino)methyl-5-ethyl-4,5-dihydro-5,10 - dihydroxy-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

Diluted hydrochloric acid (1 BC ) is added dropwise to a suspension of 11-(dimethylamino)methyl-5-ethyl-4,5-dihydro-5,10-dihydroxy-1H - oxepin[3', 4': 6,7] indolizino[1,2-b]quinoline-3,15(4H,13H)-dione (105 mg) in water until dissolved. The water is evaporated under reduced pressure and the residue suspended in acetonitrile (5 ml) and filtered to obtain 103 mg of the target salt, so pl. 248oC (decomp.).

1H-NMR (DMSO): 0,88 (t, 3H), of 1.85 (m, 2H), 2,84 (C, 6N), is 3.08 (d, 1H), 3,5 (d, 1H), to 4.73 (s, 2H), vs. 5.47 (DD, 2H), 7,33 (s, 1H), 7,38 (s, 1H), 7,72 (d, 1H), 8,19 (d, 1H), 8,99 (s, 1H), 9,92 (CE, 1H), of 11.45 (s, 1H).

13C-NMR (DMSO): 8,46; TO 34.36; 42,44 (3C); 50,61 (2C); 61,42; 73,35; 99,19; 108,63; 122,21; 122,36; 126,86; 129,13; 130,61; 133,09; 143,53; 144,70; 149,76; 155,98; 157,17; 159,27; 172,06.

Example 16: 5-ethyl-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepin [3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

This compound is obtained from 3-fluoro-4-methoxyaniline according to the method illustrated stages 11. i, 11. j, and 11.k example 11. Receives a yellow solid, so pl. > 250oC.

1H-NMR (DMSO): to 0.89 (t, 3H), 1.85 to (K, 2N), is 3.08 (d, 1H), 3,49 (d, 1H), 4.00 points (s, 3H), of 5.25 (s, 2H), 5,39 (d, 1H), 5,51 (d, 1H), 6,00 (s, 1H), 7,32 (s, 1H), 7,72 (d, 1H), to $ 7.91 (d, 1H), 8,58 (s, 1H).

13C-NMR (DMSO): 8,43; 36,48; 42,51; 50,68; 56,60; 61,42; 73,29; 99,25; 108,68; 113,52; 122,23; 126,33; 129,99; 130,30; 143,79; 144,70; 148,42; 151,18; 153,19; 155,19; 159,20; 172,0:6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

This compound is obtained from 3-chloro-4-methoxyaniline according to the method illustrated stages 11.i, 11.j, and 11.k example 11. Yellow solid, so pl. > 250oC.

1H-NMR (DMSO): of 0.85 (t, 3H), 1.85 to (K, 2N), to 2.55 (s, 3H), of 3.07 (d, 1H), of 3.07 (d, 1H), 3.45 points (d, 1H), 5.25 (s, 2H), 5,39 (d, 1H), 5,51 (d, 1H), equal to 6.05 (s, 1H), 7,39 (s, 1H), 8,10 (s, 1H), to 8.20 (s, 1H), at 8.60 (s, 1H).

13C-NMR (DMSO): 8,43; 20,20; 36,47; 42,49; 50,67; 61,41; 73,28; 99,87; 122,82; 126,98; 127,99; 129,60; 130,53; 131,08; 135,64; 136,56; 144,39; 147,11; 153,10; 155,85; 159,18; 172,03.

IR (KBr): 1208; 1479; 1606; 1656; 1724.

Example 18: 5-ethyl-9,10-debtor-4,5-dihydro-5-hydroxy-1H-oxepin[3',4': 6,7]indolizino [1,2-b]quinoline-3,15(4H,13H)-dione

This compound is obtained from 3,4-diferencia according to the method illustrated stages 11.i, 11.j, and 11.k example 11. Yellow solid, so pl. > 250oC.

1H-NMR (DMSO): of 0.85 (t, 3H), 1.85 to (K, 2N), of 3.07 (d, 1H), 3,47 (d, 1H), 5.25 in (s, 2H), 5,39 (d, 1H), 5,51 (d, 1H), equal to 6.05 (s, 1H), 7,39 (s, 1H), 8,15 (K, 1H), 8,25 (K, 1H), 8,68 (K, 1H).

13C-NMR (DMSO): 8,41; 36,45; 42,48; 50,68; 61,40; 73,25; 99,92; 114,14; 115,58; 122,96; 130,56; 131,46; 144,21; 145,25; 142,36; 153,41; 155,85; 159,16; 172,00.

IR (KBr): 1266; 1512; 1581; 1618; 1751.

Example 19: 7-ethyl-7,8-dihydro-7-hydroxy-N, 11N-[1,3] dioxolo[4,5-g] oxepin[3',4':6,7]indolizino[1,4-b]quinoline-9,12(14H)-dione

This compound is obtained from 3,4-methylenedioxyaniline when P CLASS="ptx2">

1H-NMR (DMSO): of 0.85 (t, 3H), 1.85 to (K, 2N), of 3.07 (d, 1H), 3.45 points (d, 1H), 5,20 (s, 2H), 5,39 (d, 1H), 5,51 (d, 1H), 6,00 (s, 1H), 6.30-in (s, 1H), 7,30 (s, 1H), 7,49 (d, 2H), to 8.45 (s, 1H).

13C-NMR (DMSO): 8,43; 36,49; 42,56; 50,58; 61,42; 73,31; 98,87; 102,75; 103,33; 104,92; 121,76; 125,74; 128,59; 130,33; 145,08; 146,69; 148,78; 150,19; 151,49; 155,90; 159,24; 172,08.

IR (KBr): 1248; 1459; 1606; 1731.

Example 20: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepin [3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

This compound is obtained from 3-chloro-4-methoxyaniline according to the method illustrated stages 11.i, 11.j, and 11.k example 11. White solid, so pl. > 250oC.

1H-NMR (DMSO): of 0.85 (t, 3H), 1.85 to (K, 2N), of 3.07 (d, 1H), 3.45 points (d, 1H), 4,01 (s, 3H), with 5.22 (s, 2H), 5,39 (d, 1H), 5,51 (d, 1H), 6,02 (s, 1H), 7,31 (s, 1H), 7,68 (s, 1H), to 8.20 (s, 1H), 8,55 (s, 1H).

13C-NMR (DMSO): 8,82; 36,27; 42,30; 50,48; 56,69; 61,23; 73,08; 99,16; 107,44; 122,16; 127,12; 128,12; 128,25; 130,02; 130,53; 143,29; 144,37; 151,12; 153,29; 155,71; 158,98; 171,84.

IR(KBr): 1056; 1256; 1483; 1592; 1657; 1747.

Example 21: 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepin [3',4': 6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

This compound is obtained from 4-methoxyaniline according to the method illustrated stages 11.1, 11.j, and 11.k example 11. Yellow solid, so pl. > 250oC.

1H-NMR (DMSO): of 0.85 (t, 3H), 1.85 to (K, 2N), of 3.07 (d, 1H), 3.45 points (d, 1H is): 8,45; 36,48; 42,51; 50,64; 55,92; 61,42; 73,33; 99,01; 106,49; 122,02; 123,19; 129,59; 130,20; 130,43; 144,17; 144,94; 150,40; 155,92; 158,31; 159,26; 172,07.

IR(KBr): 1251; 1604; 1655; 1735.

Example 22: 9,11-dichloro-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin [3',4': 6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

This compound is obtained from 3,5-dichloraniline according to the method illustrated stages 11.i, 11.j, and 11.k example 11. Yellow solid, so pl. > 250oC.

1H-NMR (DMSO): of 0.85 (t, 3H), 1.85 to (K, 2N), of 3.07 (d, 1H), 3.45 points (d, 1H), and 5.30 (c, 2H), 5,41 (d, 1H), of 5.55 (d, 1H), between 6.08 (c, 1H), 7,41 (c, 1H), 8,05 (c, 1H), 8,21 (s, 1H), 8,91 (c, 1H).

13C-NMR (DMSO): 8,39; 36,45; 42,51; 51,03; 61,39; 73,25; 100,62; 123,55; 124,63; 127,60; 128,08; 128,56; 132,06; 132,19; 134,53; 143,77; 148,80; 154,88; 155,82; 159,13; 171,98.

IR(KBr): 1064; 1275; 1586; 1651; 1743.

Example 23: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepin [3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

This compound is obtained from 3-fluoro-4-methylaniline according to the method illustrated stages 11. i, 11.j, and 11.k example 11. Yellow solid, so pl. > 250oC.

1H-NMR (DMSO): to 0.89 (t, 3H), 1.85 to (K, 2H), 2.49 USD (s, 3H), is 3.08 (d, 1H), 3,49 (d, 1H), total of 5.21 (s, 2H), 5,39 (d, 1H), 5,51 (d, 1H), equal to 6.05 (s, 1H), 7,39 (s, 1H), 7,87 (d, 1H), with 8.05 (d, 1H), 8,61 (s, 1H).

13C-NMR (DMSO): 8,40; 15,14; 36,45; 42,52; 50,60; 61,41; 73,28; 99,71; 112,00; 122,66; 125,38; 127,66; 129,59; 130,28; 144,49; 147,88; 152,88; 155,85; 159,18; 162,25; Ali[1,2-b]quinoline-3,15(4H,13H)-dione

This compound is obtained from 4-foronline according to the method illustrated stages 11.i, 11.j and 11.k example 11. White solid, so pl. > 250oC.

1H-NMR (DMSO): of 0.85 (t, 3H), 1.85 to (K, 2N), of 3.07 (d, 1H), 3.45 points (d, 1H), from 5.29 (s, 2H), 5,39 (d, 1H), of 5.55 (d, 1H), 6.30-in (s, 1H), 7,39 (s, 1H), 7,80 (K, 1H), 7,99 (K, 1H), 8,23 (K, 1H), 8,68 (s, 1H).

13C-NMR (DMSO): 8,40; 36,46; 42,48; 50,66; 61,41; 73,31; 99,68; 111,83; 122,75; 128,93; 130,93; 131,22; 131,93; 144,46; 145,27; 152,60; 155,89; 159,21; 172,04.

IR (KBr): 1209; 1589; 1659; 1739.

Example 25: 10-chloro-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3',4':6,7] indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

This compound is obtained from 4-Chloroaniline according to the method illustrated stages 11.i, 11.j and 11.k example 11. Yellow solid, so pl. > 250oC.

1H-NMR (DMSO): of 0.85 (t, 3H), 1.85 to (K, 2N), of 3.07 (d, 1H), 3,47 (d, 1H), 5.25 in (s, 2H), 5,39 (d, 1H), equal to 6.05 (s, 1H), 7,39 (s, 1H), 7,89 (d, 1H), 8,19 (d, 1H), 8,29 (s, 1H), 8,67 (s, 1H).

13C-NMR (DMSO): 8,40; 36,46; 42,48; 50,70; 61,42; 73,31; 100,00; 122,96; 127,31; 127,42; 128,87; 131,11; 132,12; 144,34; 146,53; 153,38; 155,88; 159,20; 172,04.

IR(KBr): 1069; 1483; 1606; 1741.

Example 26: 10-chloro-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy - 1H-oxepin[3', 4':6,7]indolizino[1,2-b]quinoline-3,15 (4H,13H)-dione

This compound is obtained from 4-chloro-3-foronline according to the method illustrated stages 11.i, 11.j and 11.kN), of 3.45 (d, 1H), 5.25 in (s, 2H), 5,39 (d, 1H), 5,61 (d, 1H), equal to 6.05 (s, 1H), 7,40 (s, 1H), to 8.20 (d, 1H), 8,40 (d, 1H), 8,68 (s, 1H).

13C-NMR (DMSO): 8,38; 36,47; 42,58; 50,71; 61,40; 73,26; 99,99; 133,59; 123,09; 124,28; 127,74; 130,64; 131,31; 144,13; 145,08; 153,57; 154,13; 155,84; 159,14; 172,00.

IR(KBr): 1488; 1583; 1655; 1743.

Example 27: 5,12-diethyl-4,5-dihydro-5,10-dihydroxy-11 - morpholinomethyl-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H) -dione

This compound is obtained from the research according to the method illustrated in example 15A. White solid, so pl. > 250oC.

1H-NMR (DMSO): of 0.85 (t, 3H), 1,87 (K, 2N), 2,53 (s, 4H), 3,03 (d, 1H), 3.45 points (d, 1H), only 3.57 (s, 4H), was 4.02 (c, 2H), free 5.01 (s, 2H), 5,38 (d, 1H), 5,52 (d, 1H), 6,0 (CE, 1H), 7,30 (s, 1H), 7,42 (d, 1H), of 7.95 (d, 1H), 8,82 (s, 1H).

13C-NMR (DMSO): 8,45; 3,49; 42,58; 53,04; 61,44; 66,33; 73,33; 98,81; 113,78; 121,81; 122,74; 126,80; 129,05; 129,91; 143,72; 145,07; 149,24; 155,06; 156,92; 159,28; 172,08.

IR(KBr): 1515; 1595; 1654; 1736.

Example 28: 5,12-diethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-1H - oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dio

28.A. 5-fluoro-4-methoxy-2-propionitrile

(This product is produced according Sugasawa T; Toyoda T; Adacji M; Saskura K, J. Am. Chem. Soc., 100 (1978), p.4842-4852). A solution of 3-fluoro-4 - methoxyaniline (20 t, 142 mmol) in anhydrous dichloromethane (200 ml) in an argon atmosphere and at 0oC is added dropwise to trichloride boron (1M in hept is so Then added dropwise in small portions propionitrile (33 ml, 420 mmol) and then trichloride aluminum (20,9 g, 156 mmol). The reaction medium is heated under reflux for 3 hours, cooled at 0oC, hydrolyzing careful addition of 2 N. hydrochloric acid (100 ml), then refluxed for 45 minutes. After cooling to 0oC get the precipitate, which is filtered, washed with dichloromethane, then extracted into water (300 ml). The aqueous phase is alkalinized to alkaline pH, extracted with dichloromethane and then ethyl acetate. The organic phase is dried (MgSO4), then evaporated to obtain the crude product, which was purified column chromatography (SiO2, AcOEt/Hpt: 1/99-20/90). Gain of 15.3 g of yellow solid.

1H-NMR (CDCl3): of 1.20 (t, 3H), 2,92 (K, 2N), 3,83 (s, 3H), 6,2 (s, 2H), 6,40 (d, 2H), 7,32 (d, 2H).

IR(KBr): 857; 1148; 1240; 1583; 1662.

28.b. ethyl-4-ethyl-7-fluoro-2-hydroxy-6-methoxy-3-quinoline-carboxyla

A solution of 5-fluoro-4-methoxy-2-propylaniline (15.3 g, 77.5 mmol) and triethylamine (of 13.9 ml, 100 mmol) in anhydrous acetonitrile (110 ml) in an argon atmosphere and at 0oC is added dropwise to a solution of ethylmaleimide (12.9 ml, 100 mmol) in anhydrous acetonitrile (30 meta sodium (obtained from 1.8 g, 78 mmol of sodium in 80 ml of ethanol, then leave to mix for 12 hours at ambient temperature. The reaction mixture was poured into a mixture of ice water (100 ml) and stirred for 2 hours, then the precipitate is filtered and washed with water, ethanol and ether. Get to 19.4 g of a white solid.

1H-NMR (CDCl3): 1,25 (m, 6N), 2,78 (K, 2H), 3,92 (s, 3H), 4,30 (K, 2N), to 7.15 (d, 2H), 7,40 (d, 2H), 11,93 (s, 1H).

IR (KBr): 786; 1083; 1410; 1521; 1644; 1725.

28.c. ethyl-2-chloro-4-ethyl-7-fluoro-6-methoxy-3-chinainternational

A suspension of ethyl-4-ethyl-7-fluoro-2-hydroxy-6-methoxy-3-chinainternational (19,4 g of 0.066 mol) in phosphorylchloride (243 ml) is heated under reflux for 6 hours. Phosphorylchloride distilled off. The reaction mixture was poured into a mixture of ice water, extracted with dichloromethane to solubilize. The organic phase is washed with water, then saturated sodium chloride solution. The organic phase is dried on magnesium sulfate and the solvent is evaporated. The residue is suspended in ether and neprevyshenie the original product (4 g) is filtered off. The filtrate is evaporated and the residue purified column chromatography (SiO2, AcOEt/Hpt: 5/95-20/80). Get to 10.9 g of a white solid.

1H-NMR (CDCl3): 1,30 (ASS="ptx2">

28.d. 2-chloro-4-ethyl-7-fluoro-6-methoxy-3-kinalimutan

A solution of ethyl-2-chloro-4-ethyl-7-fluoro-6-methoxy-3-chinainternational (10.8 g, 35 mmol) in anhydrous dichloromethane (200 ml) is treated dropwise at ambient temperature in an argon atmosphere by diisobutylaluminium (1M in dichloromethane, 65 ml, 65 mmol), then heated to 40oC for 4 hours. Cooled to 0oC, carefully add 20% aqueous solution of Rochelle salt and dichloromethane (200 ml) and stirring is continued for 1 hour. Decanted, washed three times with water and the organic phase is dried on magnesium sulfate and the solvent is evaporated. The residue is purified column chromatography (SiO2, AcOEt/Hpt: 5/95 - 50/50). Get 6 g of a white solid.

1H-NMR (CDCl3): of 1.28 (t, 3H), 3,25 (K, 2N), Android 4.04 (s, 3H), of 4.77 (d, 2H), 5,27 (t, 1H), 7,55 (d, 2H), 7,73 (d, 2H).

IR(KBr): 840; 864; 1023; 1232; 1267; 1317; 1444; 1511; 1569.

28. e. 5,12-diethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepin [3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

2-chloro-4-ethyl-7-fluoro-6-methoxy-3-kinalimutan connect with connection (M), as described in stage 11.j. example 11. Received related product cyclist according to the procedure of stage 11.k. Receives a yellow solid, so pl. > 275

1C-NMR (CF3COOD): 9,03; 14,20; 26,68; 38,77; 43,98; 53,79; 58,27; 64,73; 77,93; 106,85; 110,15; 128,99; 131,61; 137,32; 141,23; 144,13; 154,79; 158,32; 160,25; 160,81; 179,30.

IR(KBr): 1013; 1068; 1265; 1466; 1514; 1601; 1655; 1748.

Example 29: 5-ethyl-4,5-dihydro-5-hydroxy-12-methyl-1H-oxepin[3',4':6, 7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

2-acetylation use the procedures described in examples 28.b., 28. C. and 28. d. to obtain 2-chloro-4-methyl-3-kinalimutan. It is associated with connection (M), as described in stage 11.j. example 11. Received related product cyclist according to the procedure of stage 11.k. Receives a yellow solid, so pl. > 260oC.

1H-NMR (DMSO): of 0.87 (t, 3H), 1,87 (K, 2N), 2,78 (s, 3H), 2,80 (d, 1H), 3,55 (d, 1H), 5,27 (s, 2H), 5,42 (d, 1H), 5,52 (d, 1H), 6,04 (s, 1H), 7,39 (s, 1H), of 7.75 (t, 1H), 7,88 (t, 1H), 8,13 (d, 1H), of 8.25 (d, 1H).

13C-NMR (DMSO): 8,23; 36,26; 42,36; 62,00; 73,11; 78,65; 79,13; 79,25; 99,52; 122,36; 124,30; 127,67; 129,54; 129,55; 129,56; 140,11; 145,06; 148,07; 152,00; 155,79; 171,89.

IR(KBr): 1649; 1751; 3404.

Example 30: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12- (4-methylpiperazine)-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15 (4H, 13H)-dione

30.a. 5-chloro-2-chloroacetyl-4-methoxyaniline

This product is produced according Sugasawa T; Toyoda T; Adacji M; Saskura K, J. Am. Chem. Soc., 100 (1978 is the first solution diethylacetanilide in hexane (164 ml, 164 mmol) is added dropwise sequentially to a solution of 3-chloro-4-methoxyaniline (23,6 g, 150 mmol) in an atmosphere of inert gas at 0oC. the Reaction medium is heated under reflux for 1 hour, then cooled to 0oC, hydrolyzing careful addition of 2 N. hydrochloric acid (90 ml), then heated under reflux for 1 hour. Wednesday again, cool and add concentrated sodium bicarbonate solution to pH 14. The solution is extracted with ethyl acetate, the organic phase is washed with water, then with an aqueous solution of salt. Dried on magnesium sulfate, filtered and evaporated under reduced pressure. The residue is extracted in isopentane, decanted, then remove insoluble material in the minimum amount of isopropyl ether and add the isopentane to precipitate the product. Filtered and dried under vacuum. Get 17,26 g brown solid.

1H-NMR (CDCl3): is 3.82 (s, 3H), 4,60 (c, 2H), 6,11 (s, 2H), 6,78 (s, 1H), 7,11 (s, 1H).

30.b. ethyl-7-chloro-4-chloromethyl-2-hydroxy-6-methoxy-3-chinainternational

Ethylmalonyl chloride (17 ml, 131 mmol) is added dropwise to a solution of 5-chloro-2-chloroacetyl-4-methoxyaniline (17 g, 73 mmol) and triethylamine (18.5 ml, 131 mmol) in anhydrous acetone, then added dropwise at 0oC solution ethylate sodium in ethanol (obtained from 1.88 g, 80 mmol of sodium in 90 ml of ethanol). Stirred for 12 hours at ambient temperature. Add 300 ml of water, stirred for further 20 minutes. The precipitate is filtered off, washed with water, ethanol and ethyl ether. After drying in vacuo get 16.7 g of a yellowish solid.

1H-NMR (DMSO): is 1.31 (t, 3H), of 3.95 (s, 3H), 4,36 (K, 2N), of 4.95 (s, 2H), 7,46 (s, 1H), 7,49 (s, 1H).

30.with. ethyl-2,7-chloro-4-chloromethyl-6-methoxy-3-quinoline-carboxylate

A suspension of ethyl-7-chloro-4-chloromethyl-3-hydroxy-6-methoxynicotinate (of 116.7 g, 50 mmol) in phosphorylchloride (100 ml) is refluxed for 6 hours. Phosphorylchloride distilled off. The residue is extracted into water and stirred for 30 minutes. The precipitate is filtered and washed with water until neutralization. The precipitate is extracted into dichloromethane and (?) a saturated solution of sodium chloride. Filter layer celite and the filtrate is decanted. The organic phase is washed with a saturated solution of sodium chloride. Dried on magnesium sulfate and filtered and evaporated under reduced pressure. Get 15,88 g brown oil.

1H-NMR (CDCl3): of 1.47 (t, 3H), 4,08 (t, 3H), 4,55 (xilt

A mixture of ethyl-2,7-chloro-4-chloromethyl-6-methoxy-3-quinoline-carboxylate (6.9 g, 20 mmol) and N-methylpiperazine (9 ml, 80 mmol) was heated to 60oC for 30 minutes. The reaction mass is diluted with water and extracted with ethyl acetate. Decanted and the organic phase is washed with water. Dried on magnesium sulfate, filtered and evaporated under reduced pressure. The residue is extracted with water, stirred for 15 minutes, filtered, washed with water and dried in vacuum. The residue is purified column chromatography (SiO2, MeOH/CH2Cl2; 5/95 - 8/92). Obtain 6.7 g of beige solid product.

1H-NMR (CDCl3): of 1.45 (t, 3H), of 2.28 (s, 3H), 2,35-2,70 (m, 8H), 3,86 (s, 2H), Android 4.04 (s, 3H), 4,48 (K, 2N), to 7.77 (s, 1H), with 8.05 (s, 1H).

30.e. 2, 7-chloro-6-methoxy-4-(4-methylpiperazine)-3-kinalimutan

Ethyl-2,7-chloro-6-methoxy-4-(4-methylpiperazine)-3-chinainternational (6 g, 14.5 mmol) is dissolved in methylene chloride (120 ml). Slowly add molar solution of diisobutylaluminium in methylene chloride (60 ml, 60 mmol). Stirred for 1 hour at ambient temperature. Pour the reaction mass slowly into 300 ml of 20% aqueous solution of Rochelle salt. Stirred for 1 hour, filtered on celite, decanted, washed organic phase feast upon Joe substance is extracted with isopropyl ether, filtered and dried in vacuum. Obtain 4.3 g of target compound in the form of a yellow solid.

1H-NMR (CDCl3): of 2.27 (s, 3H), 2,30 is 2.80 (m, 8H), is 4.03 (s, 3H), 4,08 (s, 2H), 4,96 (s, 2H), 5,95 (s, 1H), 7,37 (s, 1H), with 8.05 (s, 1H).

30. f. 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12- (4-methylpiperazine)-1H-oxepin[3', 4': 6,7] indolizino[1,2-b] quinoline-3,15(4H, 13H)-dione

2,7-chloro-6-methoxy-4-(4-methylpiperazine) -3-kinalimutan associated with connection (M), as described in stage 11.j. example II. Received related product cyclist according to the procedure described in 11.k. Receives a yellow solid, so pl. > 250oC.

1H-NMR (DMSO): of 0.87 (t, 3H), 1,84 (K, 2N), 2,53 (s, 4H), is 3.08 (d, 1H), 3,47 (d, 1H), to 3.58 (s, 4H), to 3.58 (s, 4H), 4,06 (s, 5H), and 5.30 (s, 2H), 5,42 (K, 2N), 6,03 (s, 1H), 7,31 (s, 1H), to $ 7.91 (s, 1H), is 8.16 (s, 1H).

13C-NMR (DMSO): 8,42; 36,53; 50,65; 53,30; 56,67; 62,00; 73,32; 99,31; 104,86; 122,32; 126,94; 126,70; 129,83; 130,44; 138,89; 144,22; 144,85; 151,05, 153,17; 155,92; 159,19; 172,06.

IR (KBr): 862; 1063; 1116; 1248; 1595; 1655; 1744; 3449.

Example 31: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12 - morpholinomethyl-1H-oxepin[3',4':6,7] indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

3-chloro-4-methoxyaniline can be used in the procedure described in examples 30. A. , 30.b. and 30.with. obtaining ethyl-2,7-chloro-6-methoxy-4-chloromethyl-3-hto N-methylpiperazine, then restore this solution according to the method in example 30.e. to kinalimutan. The latter is associated with connection (M), as described in stage 11.j. example 11. The resulting product binding cyclist according to the procedure described in 11. k. Get a beige solid, so pl. > 250oC.

631H-NMR (DMSO): of 0.87 (t, 3H), 1,84 (K, 2N), of 2.15 (s, 3H), 2,32 (s, 4H), 2.50 each (s, 4H), is 3.08 (d, 1H), 3,47 (d, 1H), 4,06 (s, 5H), from 5.29 (s, 2H), 5,46 (K, 2N), the 6.06 (s, 1H), 7,31 (s, 1H), 7,92 (s, 1H), 8,17 (s, 1H).

13C-NMR (DMSO): 8,42; 36,51; 42,57; 45,93; 50,66; 52,83; 55,05; 56,09; 56,72; 61,44; 73,29; 99,30; 104,89; 122,32; 126,89; 127,63; 129,85; 130,16; 138,78; 144,18; 144,81; 151,03; 153,01; 155,10; 159,17; 172,07.

IR(KBr): 1055; 1252; 1596; 1655; 1747; 3449.

Example 32: 5-ethyl-4,5-dihydro-5-hydroxy-12-(4-methyl - piperidinomethyl)-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H) -dione

Aniline can be used in the procedures described in examples 30.A., 30. b. and 30.with. to obtain ethyl-2-chloro-4-chloromethyl-3-chinainternational, which is treated according to the procedure in example 30.d. N-methylpiperazine, then restore according to the method of example 30.e. to the appropriate kinalimutan. The latter is associated with connection (M), as described in stage 11. j. example 11. The resulting product binding cyclist according to the procedure described in 11.k.), 2,32-2,60 (m, 8H), 3,05 (d, 1H), 3,48 (d, 1H), 4.09 to (K, 2N), 5,42 (d, 1H), 5,52 (d, 1H), 6,03 (CE, 1H), 7,40 (s, 1H), 7,72 (t, 1H), a 7.85 (t, 1H), 8,16 (d, 1H), 8,45 (d, 1H).

IR (KBr): 1652; 1735; 3424.

Example 33: 5-ethyl-4,5-dihydro-5-hydroxy-12-piperidino-methyl-1H-oxepin [3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

Aniline can be used in the procedures described in examples 30.A., 30. b. and 30.with. to obtain ethyl-2-chloro-4-chloromethyl-3-chinainternational, which is treated according to the procedure in example 30.d. using piperidine instead of N-methylpiperazine, then restore according to the method of example 30. e. to the appropriate kinalimutan. The latter is associated with connection (M), as described in stage 11.j. example 11. The resulting product binding cyclist according to the procedure described in 11.k. Receives a yellow solid, so pl. > 250oC.

1H-NMR (DMSO): 0,86 (t, 3H), 1,40 (CE, 2H), 1,48 (CE, 4H), 1,87 (K, 2N), of 2.50 (s, 4H), 3,05 (d, 1H), 3,48 (d, 1H), 4.04 the (K, 2N), 5,33 (s, 2H), 5,42 (d, 1H), 5,51 (d, 1H), 6,07 (CE, 1H), of 7.75 (t, 1H), the 7.85 (t, 1H), 8,15 (d, 1H), 8,45 (d, 1H).

13C-NMR (DMSO): 8,47; 23,50; 25,82; 36,50; 42,50; 50,68; 54,47; 58,00; 61,42; 73,35; 99,55; 122,61; 125,31; 127,58; 129,54; 129,55; 129,56; 129,57; 140,49; 144,95; 148,63; 152,41; 155,90; 159,23, 172,07.

IR (KBr): 1659; 1727; 3408.

Example 34: 5-ethyl-4,5-dihydro-5-hydroxy-12-morpholinomethyl-1 in examples 30.A., 30. b. and 30.with. to obtain ethyl-2-chloro-4-chloromethyl-3-chinainternational, which is treated according to the procedure in example 30.d. using the research instead of N-methylpiperazine, then restore according to the method of example 30. e. to the appropriate kinalimutan. The latter is associated with connection (M), as described in stage 11.j. example 11. The resulting product binding cyclist according to the procedure described in 11.k. Receives a yellow solid, so pl. > 250oC.

1H-NMR (DMSO-d6): (M. D.): 0,86 (t, 3H), 1,87 (K, 2N), 3,05 (d, 1H), 3,30 (s, 4H), 3,49 (d, 1H), 3,55 (CE, 4H), 4,10 (K, 2N), to 5.35 (s, 2H), of 5.40 (d, 1H), 5,54 (d, 1H), 6,04 (s, 1H), 7,72 (t, 1H), a 7.85 (t, 1H), is 8.16 (d, 1H), of 8.47 (d, 1H).

13C-NMR (DMSO): 8,42; 36,51; 42,57; 50,68; 53,51; 56,06; 61,42; 66,41; 73,34; 99,56; 122,64; 125,25; 127,56; 129,81; 139,55; 144,92; 148,62; 152,39; 155,89; 159,21; 172,05.

IR (KBr): 1657; 1729; 3347.

Example 35: 5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-12-(4 - methylpiperazine)-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H, 13H)-dione

4-ftoranila you can use the procedures described in examples 30.A. , 30. b. and 30.c. to obtain ethyl-2-chloro-4-chloromethyl-6-fluoro-3-chinainternational, which is treated according to the procedure in example 30.d. N-methylpiperazine, then restore according to the method of example 30A 11. The resulting product binding cyclist according to the procedure described in 11.k. Receives a yellow solid, so pl. > 275oC.

1H-NMR(DMSO): of 0.87(t, 3H), 1.85 to (K, 2N), of 2.15 (s, 3H), 2,31 (m, 4H), of 2.50 (m, 4H), of 3.07 (d, 1H), 3,48 (d, 1H), Android 4.04 (m, 2H), 5,31 (s, 2H), of 5.40 (d, 1H), of 5.53 (d, 1H), equal to 6.05 (s, 1H),7,38 (s, 1H), to 7.77 (m, 1H), 8,19 (m, 2H).

13C-NMR (DMSO): 8,43; 36,51; 42,54; 45,89; 50,67; 52,92; 54,93; 55,92; 73,32; 99,56; 122,69; 130,43; 132,40; 139,69; 144,70; 145,84; 152,19; 155,90; 159,17; 172,05.

IR (KBr): 836; 1051; 1217; 1291; 1612; 1662; 1726.

Example 36: 5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-12-morpholinomethyl - 1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

4-ftoranila you can use the procedures described in examples 30.A. , 30. b. and 30.with. to obtain ethyl-2-chloro-4-chloromethyl-6-fluoro - 3-chinainternational, which is treated according to the procedure in example 30.d. using the research instead of N-methylpiperazine, then restore according to the method of example 30.e. to the appropriate kinalimutan. The latter is associated with connection (M), as described in stage 11.j. example 11. The resulting product binding cyclist according to the procedure described in 11.k. Get a beige solid, so pl. > 250oC.

1H-NMR (DMSO-d6): (M. D.): 0.87 (m, 3H), of 1.85 (m, 2H), of 2.51 (m, 4H), 3,06 (d, 1>NMR(DMSO): 8,40; 36,47; 42,52; 50,59; 53,40; 56,14; 61,44; 66,41; 73,29; 99,58; 109,05; 109,28; 120,11; 120,37; 122,68; 128,53; 130,53; 132,43; 139,13; 144,62; 145,79; 152,07; 155,94; 159,14; 161,59; 172,04.

IR (KBr): 834; 860; 1061; 1118; 1215; 1286; 1516; 1609; 1658; 1734.

Example 37: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(4 - methylpiperazine)-1H-oxepin[3', 4': 6,7] indolizino[1,2-b] quinoline-3,15(4H, 13H)-dione

3-fluoro-4-methylaniline, you can use the procedures described in examples 30. A., 30.b. and 30.with. to obtain ethyl-2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-chinainternational, which is treated according to the procedure in example 30.d. N-methylpiperazine, then restore according to the method of example 30. e. to the appropriate kinalimutan. The latter is associated with connection (M), as described in stage 11.j. example 11. The resulting product binding cyclist according to the procedure described in 11.k. Receives a yellow solid, so pl. > 260oC.

1H-NMR (CDCl3): and 1.00 (t, 3H), 2,00 (K, 2N), to 2.35 (s, 3H), of 2.50 (s, 3H), 2,61 (m, 8H), 3.33 and (d, 1H), 3,39 (d, 1H), 3,97 (d, 1H), 4,07 (d, 1H), 5,17 (d, 1H), 5,38 (d, 1H), 5,52 (d, 1H), 5,63 (d, 1H), 7,13 (d, 1H), 7,28 (s, 1H), to 7.99 (d, 1H).

IR (KBr): 1652; 1747; 3430.

Example 38: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12 - morpholinomethyl-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H) -dione

3-fluoro-4-aniline mo is ethyl-3-chinainternational, which is treated according to the procedure in example 30. d. using the research instead of N-methylpiperazine, then restore according to the method of example 30.e. to the appropriate kinalimutan. The latter is associated with connection (M), as described in stage 11.j. example 11. The resulting product binding cyclist according to the procedure described in 11.k. Receives a yellow solid, so pl. > 260oC.

1H-NMR (DMSO + CDCl3): and 1.00 (t, 3H), 2,02 (K, 2N), to 2.57 (s, 3H), 2,60 (s, 4H), 3,23 (d, 1H), 3.45 points (d, 1H), 3,75 (s, 4H), 4,11 (s, 2H), 5,44 (s, 2H), vs. 5.47 (d, 1H), 5,65 (d, 1H), 7.62mm (s, 1H), 7,73 (d, 1H), 8,24 (d, 1H).

13C-NMR (CF3CO2OD): 8,35; 13,93; 16,01; 22,24; 25,29; 38,18; 43,42; 54,19; 56,04; 56,74; 64,16; 65,09; 66,48; 108,29; 108,57; 128,07; 128,70; 129,90; 135,64; 138,03; 139,86; 141,10; 141,56; 147,78; 158,30; 161,87; 178,72.

IR (KBr): 117; 1609; 1654; 1750; 3437.

Example 39: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12 - piperidinomethyl-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H) -dione

3-fluoro-4-aniline, you can use the procedures described in examples 30. A. , 30.b. and 30.with. to obtain ethyl-2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinoline-carboxylate, which is treated according to the procedure in example 30. d. using piperidine instead of N-methylpiperazine, then restore according to method p. the. the example 11. The resulting product binding cyclist according to the procedure described in 11.k. Receives a yellow solid, so pl. > 260oC.

1H-NMR (CF3CO2D): 1,09 (s, 3H), 1.70 to (t, 1H), 2,03 (m, 5H), of 2.25 (s, 2H), 2,70 (s, 3H), 3,88 (d, 1H), 4,01 (CE, 2H), and 5.30 (K, 2N), the 5.65 (d, 1H), 5,96 (d, 1H), 6,10 (s, 2H), 8,16 (d, 1H), 8,35 (s, 1H), 8,61 (s, 1H).

13C-NMR (CF3CO2D): 8,47; 16,07; 20,93; 22,18; 24,76; 38,28; 43,53; 54,30; 56,12; 58,33; 64,24; 77,56; 108,37; 111,30; 128,20; 129,02; 129,98; 135,60; 138,29; 139,90; 141,60; 142,26; 147,57; 158,28; 161,90; 167,63; 170,31; 178,82.

IR (KBr): 1605; 1728; 3390.

Example 40: 8-ethyl-2,3,8,9-tetrahydro-8-hydroxy-16-(4-methylpiperazine) -11, 12H- (1, 4) like (2, 3-g) oxepin [3',4':6,7]indolizino[1,2-b]quinoline-10,13(15H)-dione

3,4-metilendioxifenil you can use the procedures described in examples 30. A. , 30.b. and 30.with. to obtain ethyl-2-chloro-4-chloromethyl-6,7-Ethylenedioxy-3-chinainternational, which is treated according to the procedure in example 30. d. N-methylpiperazine, then restore according to the method of example 30.e. to the appropriate kinalimutan. The latter is associated with connection (M), as described in stage 11.j. example 11. The resulting product binding cyclist according to the procedure described in 11.k. Receives a yellow solid, so pl. > 260oC.

13C-NMR (DMSO): 8,45; 24,80; 36,51; 42,48; 45,90; 50,45; 52,98; 54,91; 56,10; 61,44; 64,43; 73,30; 99,03; 109,46; 113,51; 121,95; 123,51; 127,76; 137,99; 145,00, 145,14; 145,27; 147,24; 150,53; 155,90; 159,18; 172,27; 177,00.

IR (KBr): 1656; 1743; 3422.

Example 41: 9-chloro-5-ethyl-for-4,5-dihydro-5-hydroxy-12 - morpholinomethyl-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)- dione

3-chloro-4-aniline, you can use the procedures described in examples 30.A., 30.b. and 30.with. obtaining ethyl-2,7-dichloro-4-chloromethyl-6-fluoro-3 - chinainternational, which is treated according to the procedure in example 30.d. using the research instead of N-methylpiperazine, then restore according to the method of example 30.e. to the appropriate kinalimutan. The latter is associated with connection (M), as described in stage 11.j. example 11. The resulting product binding cyclist according to the procedure described in 11.k. Get a beige solid, so pl. > 250oC.

1H-NMR (CF3COOD): 1,09 (t, 3H), 2,30 (m, 2H), 3,50 (d, 1H), 3,90 (d, 1H), 3,98 (d, 4H), 4,36 (s, 4H), 5,38 (K, 2N), 5,64 (d, 1H), 5,96 (d, 1H), 6,23 (K, 2N), to 8.57 (d, 1H), 8,69 (s, 1H), cent to 8.85 (d, 1H).

13C-NMR (CF3COOD): 8,10; 37,80; 43,11; 54,31; 55,78; 63,75; 65,11; 77,06; 128,28; 129,55; 130,33; 136,26; 137,11; 138,40; 139,67; 139,85; 148,58; 157,54; 159,74; 161,31; 178,00.

IR (KBr): 848; 1042; 1230; 1609; 1658; �-3,15(4H,13H)-dione

A mixture of ethyl--hydroxy-- (8-hydroxymethyl-imigresen[1,2-b]quinoline-9-(11N) -one-7-yl)-propionic acid (19.5 g, 52 mmol) and L-(-)- -methylbenzylamine (12,12 g, 100 mmol) in absolute ethanol (11) is boiled, subjected to hot filtration, and allowed to stand for 68 hours. The precipitate is filtered and washed with ethanol and ether to obtain 9.8 g of a white solid. Analysis of affinity chromatography high pressure on chiral phase ("chiral HPLC on column Chiral-AGP (Chromthech, Stockholm, Sweden) 100 x 4 mm, with 2% acetonitrile as eluent in 10 mm phosphate buffer at pH of 6.9, eluent peaks at 4.5 and 7.5 min) revealed two peaks, covering, respectively, 24% and 76% of the total area of these two peaks. The solid is extracted in 93% ethanol (350 ml) at reflux, then allowed to stand for 48 hours. The precipitate is filtered off, then washed with ethanol and ether to obtain 4.8 g of a white solid substance that gives two peaks, covering, respectively, 9% and 91% of the total area of these two peaks, when chiral HPLC. The solid is extracted in 50% ethanol (48 ml) at reflux, then allowed to stand for 48 hours. The precipitate is filtered off, then washed with ethanol and ether to obtain 2.7 g of a white solid obrabatyvat, enrich diastereoisomers, extract in distilled water (20 ml), acetic acid (0.35 ml, 6.4 mmol) for 15 minutes. The precipitate is filtered off, washed with water, acetone and ether, then dried in vacuum at 80oC to obtain 1.1 g of a white solid. This substance is extracted in absolute ethanol (55 ml) was added concentrated hydrochloric acid (11,5 N., 11 ml) to give a yellow solution, which was stirred at ambient temperature for 68 hours. The residue, thus obtained, filtered and washed with water, ethanol and ether, then dried in vacuum at 80oC to obtain 770 mg of enantiomerically enriched 5-ethyl-4,5-dihydro-5 - hydroxy-1H-oxepin[3', 4': 6,7]indolizino[1,2-b]quinoline-3,15(4H, 13H)-dione. Analysis of chiral HPLC (column Chiral-AGP, elution with a gradient of 2-5% acetonitrile in 10 mm phosphate buffer at pH of 6.9, eluent peaks at 15 and 20 minutes) showed the enantiomeric excess of 98%. The above procedure is repeated with the substitution of L - ( -) - methylbenzylamine D - (+) - methylbenzylamine. So get the other enantiomer of 5-ethyl-4,5-dihydro-5-hydroxy - 1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione.

Using the methods described above can byteposition products:

10-benzyloxy-5,12-diethyl-4,5-dihydro-5-hydroxy-1H - oxepin[3',4':6,7] indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

5,12-diethyl-4,5-dihydro-5,10-dihydroxy-1H-oxepin[3',4':6,7]indolizino [1,2-b]quinoline-3,15(4H,13H)-dione;

5,12 - diethyl-4,5-dihydro-5,10-dihydroxy-11-dimethyl-aminomethyl-1H - oxepin[3',4':6,7]indolizino[1,2 - b]quinoline-3,15(4H,13H)-dione;

5-ethyl-4,5-dihydro-5 - hydroxy-9,10-dimethoxy-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3, 15(4H,13H)-dione;

10-bromo-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4': 6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

11-bromo-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepin [3',4':6,7] indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

5-ethyl-12-dimethylaminomethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4': 6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

5-ethyl-4,5-dihydro-5-hydroxy-1H, 3H-cyclopent[g] -oxepin[3', 4':6,7] indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

7-ethyl-7,8-dihydro-7-hydroxy-16-(4-methylpiperazine)-N, 11N-[1, 3] dioxolo[4,5-g]oxepin[3',4':6,7]indolizino[1,2-b]quinoline-9,12(14H)-dione;

5-ethyl-4,5-dihydro-5-hydroxy-12-(1-imidazolyl)-1H-oxepin [3', 4': 6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

8-ethyl-8,9-dihydro-8-hydroxy-10H, N-oxepin[3', 4': 6,7] indolizino [1,2-b]quinoline-3,15(4H,13H)-dione;

5-ethyl-4,5,9,10,11,12-hexahydro-5-hydroxy-1H, 3H-benzo is-g]-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-10,13(15 NM)-dione;

7-ethyl-7,8-dihydro-7-hydroxy-1H, N, 11N-oxepin[3', 4':6,7]indolizino [1,2-b]pyrrolo[2,3-g]quinoline-9,12(14N)-dione;

7-ethyl-7,8-dihydro-7-hydroxy-1H, N,11N-imidazo [4,5-g]oxepin [3',4': 6,7]indolizino[1,2-b]quinoline-9,12(14N)-dione;

7-ethyl-7,8-dihydro-7-hydroxy-1H,D,11H-oxepin[3',4':6,7]indolizino[1, 2-b]1,2,3-triazolo[4,5-g]quinoline-9,12(14N)-dione;

7-ethyl-7,8-dihydro-7-hydroxy - N, 11H-oxepin[3', 4': 6,7] indolizino [1,2-b]thiazolo[4,5-g]quinoline-9,12(14H)-dione;

7-ethyl-7,8-dihydro-7-hydroxy-N,11H-oxazolo[4,5-g]oxepin[3',4': 6,7] indolizino[1,2-b]quinoline-9,12(14N)-dione.

Pharmacological study of the products of this invention 1.

The test for determining the activity of DNA relaxation induced by topoisomerase 1.

All reactions carried out in reaction buffer, 20 μl containing 50 mm Tris-HCl (pH 7.5), 50 mm KCl, 0.5 mm dithiothreitol, 10 mm MgCl2, 0.1 mm Ethylenediamine-tetraoxane acid (EDTA), 30 μl/ml bovine serum albumin and 300 ng serializovani pUC19 (Pharmacia Biotech, Orsay, France), with the test compounds or without them, to test the specified concentrations. All the tested compounds dissolved first in 50 mm dimethyl sulfoxide (DMSO), other cultivation make distilled water. The final concentration of DMSO did not exceed 1%y United Kingdom) and hold for 15 minutes at 37oC. the Reaction is stopped by adding 3 μl of a mixture containing 1% sodium dodecyl sulphate, 20 mm EDTA, and 500 μg/ml proteinase K (Boehringer Mannheim, Melan, France). After an additional incubation period for 30 minutes at 37oC, 2 µl of the boot buffer containing Na2HCO3for 0.3% bromophenol blue 16% Ficoll add to the samples, which are subjected to gel electrophoresis on a 1.2% agarose At 1 V/cm for 20 hours in a buffer containing 36 mm Tris-HCl pH 7.8, 30 mm Na2PO4, 1 mm EDTA m 2 μg/ml of chloroquine. Gels stained with ethidium bromide (2 μg/ml), photographed at 312 nm UV-light photographic device and the fluorescence intensity measured by the camera bioProfil (Vilber Lourmat, Lyon, France) to determine the percentage of relaksirano DNA. Each experiment performed at least three times in duplicate.

In each experiment helical DNA plasmid incubated alone or with topoisomerase 1. The reaction is finished in the range of 15 minutes for each connection being tested or used as a control, the spiral DNA plasmid incubated in the presence of 500 μm of test compounds to the enzyme or no enzyme plus connection, when Konzentrat the th topoisomerase 1 depending on the dose.

2. The test cell proliferation

Eight tumor cell lines used in this study: L1210 (leukemia mice), HCT15 and LOVO (line cell adenocarcinoma of the colon of a person), A549 (human lung cancer), A172, U373, U87 (human glioblastoma). All of these lines obtained from the American Type Cultures Collection (ATCC), Rockville, Md. Cultures of L1210 cells in suspension were cultured in the medium Needle, modified, Dulbecco (DMEM) (BioWhitaker, Verviers, Belgium), supplemented with 10% fetal calf serum inactivated by heating, 2 mm glutamine, 50 u/ml penicillin and 50 μl/ml streptomycin. The HT29 cells grown in monolayer cultures in the environment asso (Gibco, Paisley, United Kingdom), supplemented with 10% fetal calf serum inactivated by heating, with the addition of 2 mm glutamine and 50 μg of gentamicin. Other cells were cultured in basic medium, modified Earle (EMEM; Gibco, Paisley, United Kingdom), supplemented with 5% fetal calf serum inactivated by heating, 2 mm glutamine, 50 u/ml penicillin and 50 µg/ml streptomycin. All cell lines were cultured at 37oC in humidified atmosphere containing 95% air and 5% CO2.

Inhibition of tumor cell lines determined by MTT-test, 1500 whom tablet (level tissue culture: 96 wells, flat bottom) for 24 hours before processing the test compounds. For studies of dose-response, cells incubated with each test compound or with an appropriate solvent (control) for 48 hours in the pool final concentration of 110-10- 110-4M. All compounds are dissolved immediately before use in dimethyl sulfoxide (DMSO) at a concentration of 50 mm. Other breeding medicines perform in culture medium. The final concentration of DMSO never exceed 0.2% (vol. /about.). As control solutions drug substitute for the solvent, which is serially diluted in the same manner as the test compounds.

After an incubation period, add a marker reagent MTT (3-[4,5-dimethylthiazol-2-yl] -2,5 - diphenyltetrazolium; Thiazol blue, Sigma M 565, Sigma, St. Louis MO) at a final concentration of 0.3 mg/ml in each well. Cells incubated for 4 hours at 37oC in humidified atmosphere. This stage allows the mitochondrial dehydrogenases of living cells to turn yellow salt tetrazole MTT into purple crystals formazan. The supernatant is removed and the formed crystals formazan solubilizing using DMSO. The obtained colored restituito spectrophotometer. Data concerning proliferation, expressed as percentage of living cells in treated wells divided by the living cells in the control. Each point represents the average of three independent experiments, and each experiment gives 6 definitions.

For other cell lines (HTC15, LOVO, A549, A172, U373, U87) 1000-2000 cells seeded in the wells of the tablet for 24 hours before treatment drugs. Their incubated with each of the test compounds or the corresponding solvent (control) for 72 hours in the pool final concentration of 110-10- 110-6M

The results expressed in percentage of proliteracy, calculated from the optical density of the cells treated with the medicinal product divided by the OD of control cells (cells treated with DMSO). As shown in Table II, the test compounds inhibited cell proliferation depending on the dose.

1. Testing in vivo

The compounds of this invention are tested in vivo using cell lines of lymphoblastic leukemia L1210 in mice. Tumor cells support through a series of intraperitoneal injections in mice DBA/2 Lafacedu, Lyon, France. In an experimental test of 106cells in 0.2 ml inj Lieut up to 4 days or 8 days. The test compound is injected intraperitoneally or intravenously at various concentrations and injectable volume adjusted to 0.1 ml/10 g body weight. Not treated with the test compound mice die between 9 and 14 days after injection of cells lymphoblastic leukemia L1210 and survival received the test compound mice observed during the continued period of up to 60 days.

This experiment carried out with 5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4': 6,7]-indolizino [1,2-b]quinoline-3,15(4H,13H)-dione. This connection increases by 50% the lifespan of mice at a concentration of between 0.32 and 2.5 mg/kg, administered intraperitoneally for 4 days and at concentrations between 0.32 and 5.0 mg/kg, administered intravenously within 8 days.

Examples of drug compounds

Liquid composition: 10 mg of the compounds according to the invention; and 3.3 g of dimethylacetamide; qsp 200 g of physiological serum.

Solid composition (in compressed form): 1 mg composition according to the invention; 75 mg of lactose powder; 20 mg microcrystalline cellulose; 3 mg colloidal silicon dioxide; and 1 mg of magnesium stearate.

The proposed composition is obtained by thorough mixing of the active agent and an inert napolnili form in the form of enantiomers or any combination of these forms,

where R1denotes lower alkyl: lowest halogenated and lower alkoxylate alkyl;

R2, R3, R4represent independently H, halogen, lower halogenated, lower alkyl, (CH2)mNR6R7, (CH2)mOR6(CH2)n[N=X], substituted or unsubstituted, where the Deputy is a lower alkyl, or R2and R3together form metalinox or ethylenoxide;

R5denotes H, halogen, lower alkyl, lower alkoxy, (CH2)mNR6R7or (CH2)n[N=X], substituted or unsubstituted, where the Deputy is a lower alkyl;

R6and R7represent independently h, lower alkyl, aryl lower alkyl, halogen lower alkyl;

R9denotes lower alkyl, arylalkyl;

R16denotes H or or21;

R17indicates OR6;

R18and R19represent independently H, halogen, lower alkyl, lower alkoxy or hydroxy;

R20denotes H or halogen;

R21represents H, lower alkyl, SNO;

m is an integer between 0 and 6;

n = 1 or 3;

[N= X] denotes a substituted or neziklicescoy group and selected from the group consisting of O, S, CH2CH, NH, NR9;

or its pharmaceutically acceptable salt.

2. Connection on p. 1, wherein R1denotes an ethyl group, or its pharmaceutically acceptable salt.

3. Connection on p. 2, characterized in that the said compound is a compound of formula I, or its pharmaceutically acceptable salt.

4. Connection on p. 2, characterized in that the said compound is a compound of formula II, or its pharmaceutically acceptable salt.

5. Connection on p. 3, wherein R2and R3represent independently H, lower alkyl, halogen, lower halogenated or (CH2)mOR6or R2or R3together form methylenedioxy or Ethylenedioxy; R4and R5represent independently H, lower alkyl (CH2)mNR6R or (CH2)n[N=X], unsubstituted or substituted lower alkyl; or its pharmaceutically acceptable salt.

6. Connection on p. 5, wherein R4represents H or (CH2)mNR6R, where R6and R7represent independently H or lower alkyl and R5denotes h, lower alkyl or (CH2)n[N=X], sameem; or its pharmaceutically acceptable salt.

7. Connection on p. 6, wherein R2denotes H or halogen, and R3represents H, lower alkyl, halogen or or6where R6represents H, lower alkyl or lower arylalkyl; or its pharmaceutically acceptable salt.

8. Connection on p. 7, wherein R2denotes H, chlorine or fluorine; R3represents H, fluorine, chlorine, methyl or methoxy; or its pharmaceutically acceptable salt.

9. Connection on p. 6, wherein R2and R3form together methylendioxy or Ethylenedioxy; or its pharmaceutically acceptable salt.

10. Connection on p. 3, characterized in that it is chosen from the products corresponding to the following formula:

-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4':6,7]-indolizino[1,2-b] quinoline-3,15(4H,13H)-dione

-5,12-diethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4': 6,7] -indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-8-ethyl-2,3,8,9-tetrahydro-8-hydroxy-10H, N-[1,4] like[3',4':6,7] -indolizino[1,2-b]quinoline-10,13-(15 NM)-dione

-10-benzyloxy-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-5-ethyl-4,5-dihydro-5,10-dihydroxy-1H-oxepin[3', 4': 6,7] -indolizino[1,2-who[1,2-b]quinoline-3,15(4H,13H)-dione

-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepin[3', 4':6,7] -indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepin[3', 4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-5-ethyl-9,10-debtor-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-7-ethyl-7,8-dihydro-7-hydroxy-N, 11N-[1,3] dioxolo[4,5-q]oxepin[3', 4':6,7]-indolizino[1,2-b]quinoline-9,12(4H)-dione

-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepin[3', 4':6,7] -indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepin[3',4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-9,11-dichloro-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepin[3', 4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-10-chloro-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-10-chloro-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-1H-oxepin[3',4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-5,12-diethyl-4,5-dihydro-5,10-dihydroxy-11-morpholino-methyl-1H-oxepin[3',4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione
-5-ethyl-4,5-dihydro-5-hydroxy-12-methyl-1H-oxepin[3',4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperazine)-1H-oxepin[3',4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-morpholinomethyl-1H-oxepin[3',4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-5-ethyl-4,5-dihydro-5-hydroxy-12-(4-methylpiperazine)-1H-oxepin[3'.4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-5-ethyl-4,5-dihydro-5-hydroxy-12-piperidinomethyl-1H-oxepin[3',4':6,7] -indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-5-ethyl-4,5-dihydro-5-hydroxy-12-morpholinomethyl-1H-oxepin[3', 4':6,7] -indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperazine)-1H-oxepin[3',4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-12-morpholinomethyl-1H-oxepin[3', 4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperazine)-1H-oxepin[3',4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-morpholino-methyl-1H-oxepin[3',4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-piperidinol azidomethyl)-10H, N-(1,4-like(2,3-q)oxepin[3', 4': 6,7] -indolizino[1,2-b] quinoline-10,13(15 NM)-dione

-9-chloro-5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-12-morpholinomethyl-1H-oxepin[3',4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione, or its pharmaceutically acceptable salt.

11. Connection on p. 4, wherein R2and R3represent independently H, lower alkyl, halogen, lower halogenated or (CH2)mOR6or R2or R3together form methylenedioxy or Ethylenedioxy; R4and R5represent independently H, lower alkyl, (CH2)mNR6R7or (CH2)n[N=X], unsubstituted or substituted lower alkyl; R20denotes H or R17indicates OR6where R6denotes H or lower alkyl, or its pharmaceutically acceptable salt.

12. Connection on p. 10, wherein R4represents H or (CH2)mNR6R7where R6and R7represent independently H or lower alkyl; R5denotes h, lower alkyl or (CH2)n[N=X], unsubstituted or substituted lower alkyl; [N=X], is piperazinil or morpholinium and R17indicates OR6where R6denotes H or lower alkyl; or pharmacologie; R3represents H, lower alkyl, halogen or or6where R6represents H, lower alkyl or lower arylalkyl, or its pharmaceutically acceptable salt.

14. Connection on p. 12, wherein R2denotes H, chlorine or fluorine; R3represents H, fluorine, chlorine, methyl or methoxy; or its pharmaceutically acceptable salt.

15. Connection on p. 11, wherein R2and R3form together dioxymethylene or dioxyethylene; or its pharmaceutically acceptable salt.

16. Connection on p. 4, characterized in that the said compound is selected from the products corresponding to the following formula:

-tert-butyl--ethyl--hydroxy--(8-hydroxymethyl-9-oxo(11N)-indolizino-[1,2-b]quinoline-7-yl)-propionate

-ethyl--ethyl--hydroxy--(8-hydroxymethyl-9-oxo(11N)-indolizino-[1,2-b]quinoline-7-yl)-propionate

--ethyl--hydroxy--(8-hydroxymethyl-9-oxo(11N)-indolizino-[1,2-b] quinoline-7-yl)-propionic acid

-methyl--ethyl--hydroxy--(8-hydroxymethyl-9-oxo(11N)-indolizino-[1,2-b]quinoline-7-yl)-propionate

-ethyl-ethyl -,-debtor--hydroxy--(8-hydroxymethyl-9-oxo(11N)-indolizino-[1,2-b]quinoline-7-yl)-propionate

-ethyl--ethyl--hydroxy--(8-hydroxymethyl-9-oxo(11N)-indolizino-[1,2-b]quinoline-7-yl)-the
--ethyl--(12-ethyl-8-hydroxymethyl-9-oxo(11N)-indolizino[1,2-b] quinoline-7-yl) - hydroxy-propionic acid

--(12-benzyloxy-8-hydroxymethyl-9-oxo(11N)-indolizino-[1,2-b] quinoline-7-yl)--ethyl--hydroxypropionic acid(E) or its pharmaceutically acceptable salt.

17. The method of obtaining the compounds of formulas I and II according to any one of paragraphs.1 to 16, characterized in that hydroxylation of camptothecin General formula

< / BR>
where R1, R2, R3, R4, R5and R20have the above values,

restore with getting hydroxylate General formula

< / BR>
where R1, R2, R3, R4, R5and R20have the above values,

bond carbon-carbon adjacent to the carbinol formed so join And split with a suitable oxidant such a way as to obtain a compound of the formula IN the

< / BR>
where R1, R2, R3, R4, R5and R20have the above values,

with the subsequent processing of functional alkylating agent and the formyl group of the compounds of formula split In obtaining-hydroxyether General formula

< / BR>
where R1, R2, R3, R4, R5, R18and R20is ISSI arylalkyl;

further, the compound of the General formula cyclist obtaining-hydroxylating compounds of General formula D

< / BR>
where R1, R2, R3, R4, R5, R18, R19and R20have the above values, which disclose with obtaining the compounds of formula E

< / BR>
where R1, R2, R3, R4, R5, R18, R19and R20have the above values;

R16indicates OR21where R21denotes H or lower alkyl;

R17indicates OR6;

R6represents H, lower alkyl, lower arylalkyl.

18. Method of producing compounds of the formula I or II according to any one of paragraphs.1 to 16, characterized in that conduct the interaction of compounds of General formula M

< / BR>
where R1, R18and R19have the above values;

R20denotes a hydrogen atom or halogen,

2-halogen-3-kinalimutan General formula N

< / BR>
where R2, R3, R4and R5have the above values,

X denotes a halogen atom,

obtaining the compounds of formula ON

< / BR>
where R1, R2, R3, R4, R5, R18, R19and R20and X have the above znachno above, which disclose with obtaining the compounds of formula Ie

19. Intermediate compounds of the formula I'

< / BR>
where R1denotes lower alkyl, lower alkenyl, lower quinil, lower halogenated, lower alkoxylate alkyl or lower alkylthiomethyl alkyl;

R20denotes H or halogen, R22denotes F, Cl, or lower alkoxy;

R23denotes a protective group of the primary hydroxy-group.

20. Intermediate compounds of formula M

< / BR>
where R1denotes lower alkyl, lower halogenated, lower alkoxylate alkyl;

R18and R19represent independently H, halogen, lower alkyl, lower alkoxy or hydroxy;

R20denotes H or halogen.

21. Connection on p. 20, wherein R1denotes ethyl and R18, R19and R20denote N.

22. A therapeutic composition having antitumor activity, containing as an antitumor agent, at least one connection on the PP.1 - 16.

23. A therapeutic composition which is capable of inhibiting topoisomerase I, containing as active ingredient at least one compound p is isomerase.

25. The compound of formula I or II according to any one of paragraphs.1 - 16 with antitumor activity.

Priority points:

04.03.1996 on PP.1,7,14,19,20,22-25;

21.06.1995 on PP.1 - 19 - (compound I);

04.03.1996 on PP.1 - 19 connection II;

04.03.1996 on PP.2 - 5,13;

21.06.1995 on p. 21.

 

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The invention relates to novel polycyclic compounds of General formula

< / BR>
where a represents hydrogen and b is a group of the formula

< / BR>
either a and b taken together form a cyclic group

< / BR>
which is obtained by fermentation of a strain of the species Nodulisporium МF 5954 (ATSS 74245)

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