New analogues of camptothecin, their use as medicines containing pharmaceutical compositions

 

(57) Abstract:

The invention relates to novel analogues of camptothecin, in particular to the compounds corresponding to the following formulas (I) and (II), as well as their racemic or enantiomeric forms or combinations of these forms, where the substituents have the values. The invention also relates to their use as drugs, containing pharmaceutical compositions, and their use to obtain antitumor, antiviral and antiparasitic drugs. 2 s and 5 C.p. f-crystals, 4 PL.

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Camptothecin is a naturally occurring compound that was first isolated from the leaves and bark of the Chinese plant called camptotheca acuminata (see Wall et al., J. Amer.Chem.Soc. 88:3888 (1966). Camptothecin represents Pyh connection, formed indolizino[1,2-b]quinoline fragment, fused to six-membered-hydroxyacetone. The carbon in position 20 bearing-hydroxyl group, is asymmetric and gives the molecule the rotational energy. Natural form of camptothecin has an absolute configuration of "S" carbon 20 and corresponds to the following formula:

The
is gunning line of colon tumors, lung and breast cancer (Suffness M. et al., The Alkaloids Chemistry and Pharmacology (Chemistry and pharmacology of the alkaloids), Bross, A., ed. Vol.25, p.73 (Acedemic Press, 1985)). It is assumed that the antiproliferative activity of camptothecin associated with its inhibitory activity against DNA topoisomerase I.

Indicates that hydroxylation is absolutely necessary for both in vivo and in vitro activity of camptothecin (Camptothecins: New Anticancer Agents (Camptothecin: new anticancer agents) Putmesil M. et al., ed., R. 27 (CRC Press, 1995); M. Wall et al., Cancer Res. 55:753 (1995); Hertzberg et al., J. Med.Chem. 32:715 (1982) and Crow et al., J. Med.Chem., 35: 4160 (1992)). The present invention relates to a new class of compounds camptothecin, in which hydroxylation replaces natural-hydroxylation of camptothecin. Compounds according to the present invention possess high biological activity, which is unexpected on the state of the prior development of this field.

Thus, the subject invention are new analogues of camptothecin, which differ from all known derivatives of camptothecin in the sense that they contain-hydroxylation (or open hydroxycarboxylic form) instead of hydroxyacetone (or open hydroxyarginine, having the same structural skeleton that camptothecin (i.e., indolizino[1,2-b]quinoline fragment, fused to six-membered-hydroxyacetone), whether or not containing other chemical substituents in the structure of the skeleton. Various derivatives of camptothecin well known in the art, as described next. Under-hydroxyacetone means lactone, which contains an additional carbon atom between the carbon carboxyl and the carbon bearing the hydroxyl group in hydroxyacetone.

Therefore, the analog camptothecin according to the invention can be substituted in indolizino[1,2-b]quinoline fragment (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 substitution in the closed-hydroxyacetone include the substitution of the alkyl (e.g. ethyl) - on-carbon. Examples of substitutions in the open-hydroxyacetone include alkyl substitution on the carbon substitution (for example, the amidation) by end-carboxylic acid and substitution (for example, esterification or salt formation in the final hydroxyl group.

More specifically, the subject invention is the connection of these forms, where

R1represents lower alkyl, lower alkenyl, lower quinil, lower halogenated, lower alkoxyalkyl or lower alkylthiomethyl;

R2, R3and 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, (CH2)mOR SIG6, (CH2)mSR6, (CH2)mCO2R6,

(CH2)mNR6C(O)R8, (CH2)mC(O)R8, (CH2)mOS(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 represents a 4-7-membered heterocyclic group with the nitrogen atom N, which is a member of the heterocyclic group, and X represents the remaining members, which are necessary to complete a heterocyclic group selected from the group consisting of O, S, CH2, SN, N, NR9and COR10), substituted or not substituted aryl or lower arylalkyl (i.e. substituted by one to four R lower alkylamino, lowest halogenated, lower hydroxyalkyl, lower alkoxy or lower alkoxyalkyl, or R2and R3form together a chain with 3 or 4 members in which the circuit elements selected from the group consisting of CH, CH2, O, S, N or NR9;

R5represents H, halogen, lower halogenated, lower alkyl, lower alkoxy, lower alkoxyalkyl, lower alkylthiomethyl, cycloalkyl, cycloalkyl lower alkyl, cyano, cianelli, lower alkylsulfonyl, lower hydroxyalkyl, nitro, (CH2)mC(O)R8, (CH2)mNR6C(O)R8, (CH2)mNR6R7, (CH2)mN(CH3)(CH2)nNR6R7, (CH2)mOS(O)R8, (CH2)mOC(O)NR6R7,

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

R6th aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, lower alkoxyalkyl, lower halogenated or substituted or unsubstituted aryl or lower arylalkyl (i.e. substituted one to four times on the aryl group), where the Deputy is a lower alkyl, halogen, nitro, amino, lower alkylamino, lower halogenated, lower hydroxyalkyl, lower alkoxy or lower alkoxyalkyl;

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

R9represents H, lower alkyl, lower halogenated, aryl or aryl substituted by one or more groups selected from the following radicals: lower alkyl, halogen, nitro, amino, lower alkylamino, lower halogenated, low hydroxyalkyl ISSI alkoxy, aryl or aryl substituted (i.e., having from one to four substituents in the aryl group) one or more groups selected from the following radicals: lower alkyl, lower halogenated, lower hydroxyalkyl or lower alkoxyalkyl;

R11represents lower alkyl, aryl, (CH2)mOR14, (CH2)mSR14, (CH2)2NR14R15or (CH2)m[N=X];

R12and R13represent, independently, lower alkyl, aryl, lower alkoxy, aryloxy or amino;

R14and R15represent, independently, H, lower alkyl or aryl;

R16represents H or or21;

R17is OR6or NR6R7;

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

R20represents H or halogen;

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

m is an integer from 0 to 6;

n is 1 or 2;

q is an integer from 0 to 2 and

[N= X] represents a heterocyclic group with 4-7 members, X is the chain necessary to complete the specified heterocyclic group, and selected and.

Specifically, the subject invention are compounds of formulas I and II, as defined above, where R1represents lower alkyl, lower alkenyl, lower halogenated, lower alkoxyalkyl or lower alkylthiomethyl;5represents H, halogen, lower halogenated, lower alkyl, lower alkoxy, lower alkoxyalkyl, lower alkylthiomethyl, cycloalkyl, cycloalkyl lower alkyl, cyano, cianelli, lower hydroxyalkyl, nitro, (CH2)mC(O)R8, (CH2)mNR6C(O)R8, (CH2)mNR6R7, (CH2)mN(CH3)(CH2)nNR6R7, (CH2)mOS(O)R, (CH2)mOS(O)NR6R7or (CH2)n[N= X], OC(O)[N=X], (CH2)mOC[N=X], aryl or lower arylalkyl, substituted or unsubstituted; R12and R13represent, independently, lower alkyl; R16is OR21and R18, R19and R20represent N.

Preferably R2represents H or halogen, and more preferably H, chloro or fluoro and R3represents H, lower alkyl, halogen or or6where R6represents H, lower alkyl or lower arylalkyl and preferably H, fluorine, chlorine, methyl or methoxy. Also bankrate, the subject invention are compounds of formulas I and II, in which R2represents a hydrogen or halogen atom, R3represents a halogen atom, lower alkyl or lower alkoxy, R4, R16, R18, R19and R20represents a hydrogen atoms, or their pharmaceutically acceptable salts. Aminoalkyl radical preferably chosen for R5.

More specifically, the subject invention are the products described in the examples below, and correspond to the following formulas:

hydrochloride, 5-ethyl-9,10-debtor-4,5-dihydro-5-hydroxy-12-(1,2,5,6-tetrahydropyridine)-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-12- (4-methylpiperidino)-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-12-pyrrolidinyl-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-12-(4-methylpiperazine-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-12-piperidinomethyl-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-12-dimethylaminomethyl-1H-oxer-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-12-(4-methylpiperazine)-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

- 12-benzylpiperazine-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;

- 12-(4-benzylpiperazine)-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;

- 9-chloro-5-ethyl-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;

- 12-(4-benzylpiperazine)-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;

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

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

- 12-diisobutylamine-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-9-fluoro-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;

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

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

hydrochloride, 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(1,2,5,6-tetrahydropyridine)-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-12-(4-methylpiperidino)-lH-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

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

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

- 12-(4-benzyl-Christ.
- 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidino)-lH-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione;

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

or their pharmaceutically acceptable salts.

More specifically, the subject invention are the compounds of formula II, as defined above, in which R1represents ethyl group; R2and R3represent, independently, H, lower alkyl, halogen, lower alkylhalides or (CH2)mOR6or R2and R3form together methylendioxy or Ethylenedioxy; R4and R5represent, independently, H, lower alkyl, (CH2)mNR6R7or (CH2)n[N=X], unsubstituted or substituted lower alkyl; R20is H and R17is OR6where R6represents H or lower alkyl, or NR6R7where R6and R7independently, represent H, lower alkyl, aryl or lower alkylaryl. Preferably R4represents H or (CH2)mNR6R7where R6and R7N= X], unsubstituted or substituted lower alkyl, and R17is OR6where R6represents H or lower alkyl, or pharmaceutically acceptable salt. As an example, substituted or unsubstituted [NX] here may be noted piperidyl, morpholinyl, piperazinil, imidazolyl and 4-methylpiperazine radical.

R2more preferably represents H or halogen, preferably H, chloro or fluoro; R3represents H, lower alkyl, halogen or or6where R6represents H, lower alkyl or lower alkylaryl and preferably H, fluorine, chlorine, methyl or methoxy. Also the preferred way R2and R3together form dioxymethylene or dioxyethylene.

More specifically, the subject invention are described hereinafter in the examples, the products, in particular products that comply with the following formula:

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

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

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

or their pharmaceutically acceptable salts.

As used here, the term "lower" used in relation to alkyl, alkylthio or alkoxygroup, means linear or branched saturated aliphatic hydrocarbon group containing from 1 to 6 carbons, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methylthio, ethylthio, methoxy, ethoxy. As for alkenylphenol or alkenylphenol groups, the term "lower" means a group containing from 2 to 6 carbon atoms and one or more double or triple bond, such as vinyl, allyl, Isopropenyl, penttila, hexamidine, etinilnoy, protanilla, proponila and Butyrina group. The term "cycloalkyl" means a ring of 3-7 carbons, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl with at least one aromatic ring, each ring contains at least 7 members, such as, for example, phenyl, naphthyl, antracol, biphenyl or indenyl. The term "halogen" means chlorine, bromine, iodine or fluorine. The radicals corresponding to the expressions "lower halogenated, lower cianelli, lower nitroalkyl, lower aminoalkyl, lower hydrazinolysis, lower azidoethyl, lower arylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkylthiomethyl and lower alkylsulfonyl" are substituted respectively with one to three halogen, cyano, nitro, amido, hydrazino, azido, aryl, hydroxy, lower alkoxy, lower alkylthio or lower sulfonylamino groups. Lowest acylaminoacyl may contain one or two alkyl groups and is, for example, N3, N2CH3N(CH3)2or N(CH3)(CH2CH3). Examples [N= X] include piperidinyloxy, morpholinyl, piperazinilnom and imidazolidinyl group.

As it is observed for camptothecin, the carbon atom bearing the hydroxyl function in hydroxyacetone or hydroxycarboxylic group in the compounds according to the present invention, is asymmetric. Therefore, the compounds according to the present image is t two enantiomeric forms and any combination of these forms, including "RS" racemic mixture. To simplify where structural formula does not provide a specific configuration, it should be understood that presents two enantiomeric forms and mixtures thereof.

The object of the present invention are also methods for obtaining the compounds of General formulas I and II or on the basis of camptothecin or substituted camptothecins, or by chemical synthesis.

Thus, the invention relates to a method for producing compounds of formulas I and II according to the invention and, in particular, products of the above formula, based on camptothecin or substituted camptothecins, characterized in that

- camptothecin-hydroxylation General formula

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where R1, R2, R3, R4, R5and R20have the above values,

restore to get-hydroxyestra General formula

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where R1, R2, R3, R4, R5and R20have the above values,

- formed in this way the connection And the carbon-carbon bond linking adjacent carbinol, torn by treatment with a suitable oxidizing agent to obtain a compound of the formula IN the

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where R1
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where R1, R2, R3, R4, R5, R18, R19and R20have the above values, R17is OR6where R6represents lower alkyl, cycloalkyl, lower alkylsilanes, lower alkenyl, lower alkylalkoxy or aryl, or lower alkylaryl;

- the connection specified General formula With cyclist to obtain-hydroxyacetanilide compounds of General formula D

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where R1, R2, R3, R4, R5, R18, R19and R20have the above values,

the lactone of General formula D open to obtain the compounds of formula E

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where R1, R2, R3, R4, R5, R17, R18, R19and R20have the above values, R16is OR21where R21represents H or lower alkyl, and R17is OR6or other6where R6represents H, lower alkyl, cycloalkyl, lower alkyl cycloalkyl, lower alkenyl, lower alkylalkoxy or aryl or lower alkylaryl.

Some compounds of General formula E can also be obtained by hydrolysis of the ester functions in the corresponding compounds of formula D. the Compounds of General formula E is s or lidirovali under standard conditions, well-known specialist in this field, to obtain the esters or amides of formula Ie

In the above method, the group R1, R2, R3and R4if necessary, can be protected in accordance with standard methods of protection (Greene, T., Protective Groups in Organic Synthesis (Protective groups in organic synthesis) 10-86 (John Wiley & Sons (1981)). In this way the recovery is carried out using a reducing agent in a suitable solvent, such as, for example, borohydride sodium in methanol. The stage corresponds to the formation of a connection based on connection And is implemented under oxidizing conditions, such as, for example, using leads to compounds, which lead period acid or metaperiodate sodium in a suitable solvent, such as, for example, acetic acid. Processing functionalized alkylating agent may be made using metal intermediates, for example, lithium or zinc, complex ether carboxylic acid in an anhydrous aprotic solvent such as, for example, tetrahydrofuran. The stage of formation of the lactone, which allows you to get a connection D on the basis of the connection, usually carried out under acidic conditions, for example, when printing handling the ACOM as dichloromethane or dioxane. Disclosure lactoovo ring compounds (D) to obtain compound E can be, for example, by hydrolysis under alkaline conditions followed by neutralization.

Examples of the substituted camptothecin used as starting materials, can be found in U.S. patents. 4473692, 4604463, 4894956, 5162532, 5395939, 5315007, 5264579, 5258516, 5254690, 5212317 and 5341745 and in the patent applications PCT US 91/08028, US 94/06451, US 90/05172, US 92/04611, US 93/10987, US 91/09598, EP 94/03058 and EP 95/00393 and applications to the European patent 325247, 495432, 321122 and 540099.

Thus, the invention also relates to a method for producing compounds of formulas I and II, wherein

connection with the General formula M

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where R1, R18and R19have the above meanings and R20represents a hydrogen or halogen atom,

interacts with 2-halogen-3-kinalimutan General formula N

< / BR>
where R2, R3, R4and R5have the above meanings and X represents a halogen atom,

to obtain the compounds of formula ON

< / BR>
where R1, R2, R3, R4, R5, R18, R19, R20and X have the above values,

- then compound of General formula About cyclist to get soede
and R4if necessary, can be protected in accordance with standard methods of protection (Greene, T., Protective Groups in Organic Synthesis (Protective groups in organic synthesis) 10-86 (John Wiiey & Sons 1981)). The formation of the compound Of proceeding from compounds of the General formulas M and N is carried out at a treatment known to the person skilled in the art under the name of reactions Mitsunobu (Mitsunobu) (see Mitsunobu, O. et al., Synthesis, p.1 (1981)). The hydroxyl function of compound N is substituted by a nucleophile, such as the connection M, or deprotonirovannym derived by processing a phosphine, such as triphenylphosphine, and azodicarboxylate derived, for example, diethylazodicarboxylate, in an aprotic solvent such as, for example, tetrahydrofuran or N,N-dimethylformamide. The cyclization of compounds Of preferably carried out in the presence of palladium catalyst (such as palladium diacetate) in alkaline conditions (created, for example, alkali metal acetate optionally in combination with a phase transfer agent, such as, for example, tetrabutylammonium bromide) in an aprotic solvent such as acetonitrile or N,N-dimethylformamide, at a temperature between 50 and 120o(R. Grigg et al., Tetrahedron 46, page 4003 (1990)).

Connection obsl pyridine of General formula

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where R1and R20have the meanings indicated above and R22represents a halogen atom or lower alkoxy,

protect acetaldol function to obtain compounds of General formula F

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where R1, R20and R22have the above meanings and Z and Z' groups are, independently, lower alkyl or together form a saturated hydrocarbon chain with 2 to 4 carbons;

in connection with the General formula F enter hydroxymethylene function to obtain compounds of General formula G

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where R1, R20, R22Z and Z' have the above values,

then the alcohol function of the compound of General formula G protects to obtain compounds of General formula H

< / BR>
where R1, R20, R22Z and Z' have the above meanings and R23represents a protective group of the alcohol function,

- acetal compounds of General formula N remove the protection to obtain compounds of General formula I'

< / BR>
where R1, R20, R22and R23have the above values,

the compound of formula I' is treated functionalized alkylating agent to obtain-hydroxy complex ester of General formula J

< / BR>
where R1, Rdefined in General formula II,

- break down the protective group R23in the compound of General formula J to obtain compounds of General formula

< / BR>
where R1, R18, R19, R20and R22have the above meanings and R17is OR6or other6where R6represents H, lower alkyl, cycloalkyl, lower alkylsilanes, lower alkenyl, lower alkylalkoxy or aryl, or lower alkylaryl,

the compound of General formula To cyclist in connection with the General formula L

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where R1, R18, R19, R20and R22have the above values,

and, finally,

the radical R22connection L is converted into a carbonyl to obtain compounds of General formula M

< / BR>
where R1, R18, R19, R20and R22have the above values.

Carbonyl function 4-acyl-2 - pyridine (obtained, for example, in accordance with Lammattina J. L., J. Heterocyclic Chem. 20, R. 553 (1983)) is preferably protects acetaldol function, preferably a cyclic acetal, under standard conditions known to the person skilled in the art (Greene, T., Protective Groups in Organic Synthesis (Protective groups in organic synthesis) 10-86 (John Wiley & Sons 1981)). Thus obtained intermediate of the is f, derivative which is an alcoholate, at a temperature between 0 and 100oTo obtain compounds of General formula F. the Latter may be literarure in position 3 processing aryl - or alkyllithium (for example, musicalities) in ethereal solvent such as tetrahydrofuran, at temperatures between -100 and 0oC To the thus obtained lithium intermediate connection type formulirui electrophile such as N,N-dimethylformamide, and the resulting aldehyde is treated, after hydrolysis, regenerating agent such as borohydride sodium, to obtain compounds of General formula G. the Protection of the alcohol function of the compound G carried out under standard conditions known to the person skilled in the art, to obtain compounds of General formula N. Examples of protective groups of the alcohol functions include those that form ethers (i.e., methyl, methoxymethyl, tetrahydropyranyl, 2-methoxyethoxymethyl, benzoyloxymethyl, tert-butyl and benzyl (substituted or unsubstituted) and esters (i.e., formate, acetate and isobutyrate). As other examples of protective groups are primary hydroxyl can be referenced in Greene, T. , Protective Groups in Organic Synthesis (Protective groups in organic Synthe is syshestvyut in selective conditions, preserving the integrity of the radical R23for example, by treatment in acidic conditions (for example, triperoxonane acid). Selective conditions protect and unprotect functional groups known to the person skilled in the art (Greene, T., Protective Groups in Organic Synthesis (Protective groups in organic synthesis) 10-86 (John Wiley & Sons 1981)). Treatment of compound I' functionalized alkylating agent to obtain-hydroxy complex ester of General formula J can be performed using enolate lithium or derived carboxyl zinc complex ester in an anhydrous aprotic solvent, for example tetrahydrofuran. The protective group R23compounds of General formula J is cleaved to obtain the compounds of General formula in terms of removing the protection, well-known specialist in this field. For example, when R23represents a benzyl group, an alcoholic solution of compounds of General formula J with added palladium catalyst may be subjected to an atmosphere of hydrogen at a pressure of from 0.5 to 10 bar. Cyclization of the thus obtained compounds of General formula K can be carried out in acidic conditions (e.g., processing triperoxonane acid or gazoobraznye-hydroxyacetanilide rings with 7 members, 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, when processing a warm hydrochloric acid or in the processing of trimethylsilylimidazole.

2-Halogen-3-kinalimutan General formula N can be derived from acetanilide General formula R

< / BR>
where R2, R3and R4have the meanings specified in the General formulas of the compounds I and II. In the method below, the group R2, R3and R4if necessary, can be protected in accordance with the usual methods of protection (Greene, T., Protective Groups in Organic Synthesis (Protective groups in organic synthesis) 10-86 (John Wiley & Sons (1981)).

Thus, the compounds of formula N can be obtained in the following way: N-acetimidoyl these anilines of the formula R by processing azetiliruet agent such as acetic anhydride. Thus obtained acetanilide treated at a temperature in the range from 50 to 100oC, preferably at 75oC, a reagent known to specialists in this area under the name of the reagent Vilsmeier (obtained by the interaction of phosphorus oxychloride and N,N-dimethylformamide at a temperature between 0 and 10oC) d is n 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 the 2-position of 2-chloro-3-hyalinobatrachium can be replaced by iodine or bromine by heating the product in an inert solvent, such as acetonitrile, in the presence of iodide or bromide salt (e.g. sodium iodide or tetrabutylammonium bromide). Trace amounts of acid, such as concentrated hydrochloric acid, may be necessary for the catalysis of such transformation. 2-Halogen-3-hinolincarbonova easily reduced to the corresponding 2-halo-3-kinalimutan General formula N under standard conditions known to the person skilled in the art, such as treatment in an alcohol solvent (e.g. methanol) with sodium borohydride at a temperature between 0 and 40oC.

The compounds of formula N can also be obtained in accordance with the following method: anilines of General formula R, defined above, acelerou interaction with 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 solvents in the placenta is m the process ethylmaleimide in an aprotic solvent, such as acetonitrile, in the presence of a base, such as triethylamine, is then treated with alkali in alcohol, such as sodium methylate in methanol, to obtain ethyl-2-hydroxy-3-chinainternational, substituted in position 4. It turned into ethyl-2-chloro-3-chinainternational treatment with phosphorus oxychloride. When in position 4 of the quinoline has chloromethylene group, can be carried out nucleophilic substitution by treatment with a secondary amine, such as dimethylamine, N-methylpiperazine, morpholine or piperidine. Ethyl-2-chloro-3-chinainternational then restore diisobutylaluminium in an aprotic solvent such as dichloromethane, to obtain 2-chloro-3-kinalimutan General formula N. Analogues of intermediates (N) have been described in the literature and, in particular, in PCT application 95/05427.

The subject invention are also new industrial products and, in particular, new industrial products, designed to obtain the compounds of formula I or II; compounds of formulas I' and M, as described above.

Some compounds according to the invention can be obtained by conventional means in the form of pharmaceutically acceptable salts. Acceptable salts include, CAD, sulfate, phosphate, diphosphate, hydrobromide and nitrate, or with organic acids such 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 part of the claimed scope of the present invention, when they can be used. For other examples of pharmaceutically acceptable salts can be sent to the "Pharmaceutical Salts" (Pharmaceutical salt), J. Pharm.Sci. 66:1 (1977).

Compounds of the present invention possess useful pharmacological properties. Thus, the compounds of the present invention have inhibitory activity against topoisomerase I and/or II and antitumor activity. The state of knowledge in this area suggests that the compounds according to the invention possess anti-parasitic and/or antiviral activities. Connection

according to the present invention can also be used for various therapeutic purposes.

Illustration of the pharmacological properties of the compounds of the invention can be found later in the experimental part.

Joint who ovec, with the introduction of this patient a therapeutically effective amount of the compounds of formula (I) or formula (II).

Compounds according to the invention also possess antitumor activity. They can be used to treat tumors, such as tumors expressing topoisomerase, in a patient by administration of the last therapeutically effective amount of the compounds of formula (I) or formula (II). Examples of tumors or cancers include cancer of the esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, breast, cervix, pineal endometrial, ovarian, prostate, testicular, bladder, kidney, liver, pancreas, bones, connective tissue, skin, eyes, brain and Central nervous system, as well as thyroid cancer, leukemia, disease Hodgkin (Hodgkin), lymphoma, non-related to Hodgkinhuxley, multiple myeloma, and others.

They can also be used to treat parasitic infections by inhibiting hemagluttinin (for example, when trypanosome or leishmaniasis the infections) or by inhibition of Plasmodium (e.g. malaria), as well as for treatment virusencyclo application. The subject of this application is also the use of products of formula (I) or (II), as defined above, as well as additive salts of these products of formula (I) or (II) with pharmaceutically acceptable mineral or organic acids, as medicines and pharmaceutical compositions containing as active ingredient at least one of the drugs, as defined above.

Thus, the invention relates to pharmaceutical compositions containing a compound according to the invention or its additive salt with a pharmaceutically acceptable acid, in combination with a pharmaceutically acceptable carrier in accordance with the selected route of administration (e.g. oral, intravenous, intraperitoneal, intramuscular, percutaneous or subcutaneous). The pharmaceutical composition (e.g., therapeutic) may be in solid, liquid, liposomal forms or in the form of lipid micelles.

The pharmaceutical composition may be in solid form, for example in the form of powders, pills, granules, tablets, liposomes, gelatin capsules or suppositories. The pill, tablet or gelatin capsule can be coated with a substance capable of before knogo period of time, allowing the composition to pass in undigested in the small intestine of the patient. The connection may be applied locally, for example at the location of the tumor, and may be entered in accordance with the method of sustained release (for example, the composition is a delayed release or intravenous injection). Suitable solid carriers may represent, for example, calcium phosphate, magnesium stearate, magnesium carbonate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, carboxymethylcellulose sodium, polyvinylpyrrolidine and wax. Pharmaceutical compositions containing a compound according to the invention, can be presented in liquid form, such as, for example, solutions, emulsions, suspensions or slow release formulations. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, such as polyethylene glycol, and their mixtures in various ratios in the water.

The subject invention is also the use of products of formula (I) or (II) as defined above, to obtain drugs for inhibiting topoisomerase, and, more specifically, t is edst, intended for the treatment of parasitic infections, as well as pharmaceuticals for the treatment of viral diseases.

The dose of a compound according to the present invention, intended for the treatment of the above diseases or disorders, varies in accordance with the method of administration, the age, body weight of the subject, as well as the last, and will ultimately be determined by the attending physician or veterinarian. Such amount, determined by the attending physician or veterinarian is called here "effective therapeutic amount".

Unless otherwise specified, all used here is the technical and scientific terms have the same meaning as is commonly understood by ordinary specialist in the field to which the invention relates. Similarly, all publications, patent applications, all patents and all other mentioned here, links are included in this description by reference.

The following examples are presented to illustrate the above methods and should not be construed as limiting the scope of invention.

Experimental part

Example 1: tert-butyl--ethyl--hydroxy--hydroxymethyl-9-oxo- (11N)-indolizino[1,2-b]quinoline-7-the Tria (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 mixture gently heated to 55oTo obtain a clear solution which is then stirred for 16 hours at ambient temperature. Then the solvent is evaporated under reduced pressure, the residue absorb water (250 ml), neutralized by adding acetic acid (21 ml) and left for 2 hours at 4oC. the resulting suspension is filtered and washed successively with cold water, acetone and diethyl ether, resulting after drying under reduced pressure to obtain the desired product as a white solid, so pl. 280oC.

1.b. 8-Formyloxyethyl-7-propionylcarnitine[1,2-b]quinoline-9(11H)-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 one hour at ambient temperature. Then the reaction mixture was poured into a mixture of ice/water (650 ml) and after this is isopropyl alcohol and diethyl ether, which leads after drying under reduced pressure to obtain the desired product (11.5 g) as a pale yellow solid, so pl. > 200oC (decomp.).

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

A suspension of zinc (6.5 g, 100 mmol), stir on a magnetic stirrer in anhydrous diethyl ether (50 ml) under argon, activate, adding dropwise trimethylchlorosilane (0.75 ml, 5.7 mmol). Stirring is continued for 15 minutes at ambient temperature, after which the reaction mixture is heated to boiling under reflux. After that, the heating bath is removed and added dropwise tert-butylbromide (15 ml, 100 mmol) at such a speed as to maintain the boil under reflux. External heating return in place and continue heating for one hour. The obtained ether solution reagent reformed leave to cool to ambient temperature and then transferred using a 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) under argon. The reaction mixture is stirred at the boiling reverse cold is liveout by adding saturated ammonium chloride (100 ml) and the extraction is carried out with chloroform (CH ml). The combined chloroform extracts are dried over sodium sulfate, evaporated and the residue purified by chromatography on a column of silica gel (1-2% MeOH/CH2Cl2), which leads to obtain 0.64 g (31%) of the desired product as a pale yellow solid, so pl. 146-149oC.

NMR1H (CDCl3): of 0.93 (t, 3H); to 1.37 (s, N); 1,99 (m, 2H); of 2.97 (DD, 2H); 3.5 (sextet, 1H); 5,10 (s, 2H); of 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).

NMR-FROM13(Dl3): 8,18; 27,90; 34,59; 45,34; 49,91; 58,55; 77,39; 82,42; 100,52; 127,67; 127,97; 128,10; 126,64; 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 - a-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-(11N)-she (400 mg, 1.15 mmol) in anhydrous tetrahydrofuran (20 ml) containing 10 mg of hydroquinone are heated at the boil under reflux under argon. The heating bath is removed and initiate an exothermic reaction, adding a drop of ethylbromoacetate and a small crystal of iodine. Boil support, adding dropwise ethylbromoacetate (500 μl, 4,48 mmol), then the reaction mixture is again boiled with reverse Hovannisian saturated ammonium chloride (10 ml) and methanol (30 ml). The resulting mixture was stirred for 5 minutes, then filtered and evaporated. The residue is dissolved in dichloromethane (30 ml), washed with water and dried over sodium sulfate. Then the solvent is removed and conduct purification using column chromatography (SiO2CH2Cl2/MeOH, 98/2) to give 230 mg (49%) of target compound in the form of a yellow solid, so pl. 157-161oC.

NMR1H (CDCl3): of 0.93 (t, 3H); of 1.20 (t, 3H); 2,02 (m, 2H); of 3.07 (DD, 2H); 4,11 (K, 2N) and 4.9 (sextet, 1H); to 5.08 (s, 2H); 5,23 (s, 2H); 7,45 (s, 1H); a 7.62 (t, 1H); 7,80 (t, 1H); of 7.90 (d, 1H); by 8.22 (d, 1H); at 8.36 (s, 1H).

NMR-FROM13(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; 148,28; 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-(11N)-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 hydrogen chloride in dichloromethane (100 ml). The mixture was incubated at -20oC for 16 hours. The precipitate is filtered off, washed with methanol and dried under reduced pressure, getting 662 mg (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).

NMR-FROM13(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: -ethyl--hydroxy--(8-hydroxymethyl-9-oxo- (11N)-indolizino[1,2-b]quinoline-7-yl)propionic acid

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) is added an aqueous solution of potassium hydroxide (0.1 N. , 30 ml) and the resulting suspension stirred at ambient temperature for 16 hours, getting visually transparent liquid solution, which is filtered off. The filtrate is acidified to pH 3.5 1 N. hydrochloric acid and the yellow precipitate collected by filtration, washed with water and acetone, then dried under reduced pressure, getting 415 mg (79%) of target compound in the form of a monohydrate, so pl. 165-167oC.

NMR1H (DMSO): of 0.82 (t, 3H); 2,10 (m, 2H); and 2.83 (d, 2H); 3,12 (d, 2H); 3,25 (sextet, 1H); to 4.81 (s, 2H); of 5.26 (s, 2H); 5,76 (sextet, 1H); 7,38 (s, 1H); 7,71 (t, 1H); to 7.84 (t, 1H); 8,10 (d, 1H); 8,18 (d, 1H); 8.34 per (s, 1H); 12,15 (sextet, 1H).

NMR-FROM13(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; 152,19; 156,07; 161,22; 1H)-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 suspension in methanol (50 ml) is treated with 6 N. dry hydrogen chloride in methanol (0.5 ml) and maintained at the boil under reflux until complete dissolution (4 hours). Volatile compounds are evaporated and the residue is dissolved in dichloromethane (50 ml), washed with diluted sodium hydroxide (0,05 N., 15 ml) and saturated brine (15 ml). The organic fraction is dried over sodium sulfate and evaporated. The solid residue purified by chromatography on a column of silica gel (5% MeOH/CH2Cl2) and the purified product is placed in diethyl ether, filtered and dried, giving 120 mg (58%) of target compound as a pale yellow solid product, so pl. 163-166oC.

NMR1H (CDCl3): of 0.93 (t, 3H); 2,2 (m, 2H); 3,05 (DD, 2H); to 3.49 (s, 3H); 3,62 (s, 3H); is 4.93 (s, 2H); 5,22 (d, 2H); 5,52 (s, 1H); 7,21 (s, 1H); a 7.62 (t, 1H); 7,81 (t, 1H); to $ 7.91 (d, 1H); by 8.22 (d, 1H); at 8.36 (s, 1H).

NMR13With (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.

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

PR is indolizino[1,2-b]quinoline-9(11N)-she (2.0 g, of 5.75 mmol, obtained as in example 1.b.) in the form of a suspension in anhydrous THF (10 ml) was bury under argon to a suspension of zinc (1,25 g, and 17.2 mmol) in anhydrous THF at boiling under reflux (40 ml), then added the remaining part of ethylbromoacetate. The reaction mixture was stirred at the boil under reflux for half an hour. After cooling to ambient temperature the reaction was stopped by adding a saturated solution of ammonium chloride (20 ml) and the reaction mixture was extracted with dichloromethane (3h20 ml). The combined organic extracts were dried and concentrated. The residue was placed in diethyl ether (10 ml), was filtered and was purified column chromatography (SiO2CH2Cl2/Meon, 98/2), which gives 664 mg (26%) of product as a yellow solid, so pl. 208-209oC.

NMR1H (CDCl3): of 0.91 (t, 3H); to 1.38 (t, 3H); 2,32 (m, 2H); 4,8 (sextet, 1H); to 4.38 (K, 2N); 5,09 (d, 2H); 5,13 (DD, 2H); 7,42 (s, 1H); at 7.55 (t, 1H); 7,72 (t, 1H); 7,79 (d, 1H); 8,08 (d, 1H); by 8.22 (s, 1H).

NMR13With (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-(1b] quinoline-9-(11N)-she (500 mg, of 1.43 mmol, obtained by Kingsburry 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. After 10 minutes the reaction mixture was activated by adding dropwise molar solution chloroethylamine (10 ml, 10 mmol), then added dropwise to ethylbromoacetate (1.25 ml, 11.3 mmol) and the resulting mixture is left to interact for another 5 hours. The reaction is stopped by the sequential addition of ethyl alcohol (10 ml) and a saturated solution of tartrate of potassium and sodium (10 ml). The resulting mixture is stirred for one hour, filtered and concentrated under reduced pressure. The residue is placed in dichloromethane (30 ml), washed with water, dried, concentrated and purified column chromatography (SiO2CH2Cl2/MeOH, 98/2) that give 93 mg (15%) of the desired product as a pale yellow solid, so pl. 185-188oC.

NMR1H (CDCl3): of 0.91 (t, 3H); of 1.17 (t, 3H); 1,99 (m, 2H); 2.49 USD (s, 3H); 3,10 (DD, 2H); 4,11 (K, 2N); 4,6 (sextet, 1H); 5.25 in (s, 2H); the 7.65 (t, 1H); to 7.67 (s, 1H); 7,80 (t, 1H); of 7.90 (d, 1H); by 8.22 (d, 1H); 8.34 per (s, 1H).

NMR-FROM13(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 oxo-(11H)-indolizino[1,2-b]quinoline-7-yl)propionate

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) is added dropwise acetic anhydride (70 μl, 0.7 mmol) and the resulting mixture stirred at ambient temperature for 21 hours. Volatile components are evaporated and the residue is purified chromatographically on a column of silica gel (1-2% MeOH/CH2Cl2) that give 152 mg of the target compound as a yellow solid, so pl. 195-196oC.

NMR1N (Dl3): to 0.88 (t, 3H); 1.32 to (C, N); of 1.93 (m, 2H); 2,07 (s, 3H); of 2.97 (DD, 2H); 4,8 (sextet, 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).

NMR-FROM13(CDCl3): 8,02; 21,06; 27,91; 35,05; 45,58; 50,16; 59,23; 77,52; 82,26; 100,59; 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-Etiketten (Sawada with employees, Chem.Phann.Bull.39:2574 (1991)). The target compound obtained as a bright yellow solid, so pl. >270o, N); 7,76 (t, 1H); 7,89 (t, 1H); 8,18 (d, 1H); 8,32 (d, 1H).

NMR-FROM13(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; 129,92; 130,18; 145,17; 145,82; 148,57; 152,15; 155,89; 159,26; 172,08.

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

The connection is produced by way similar to Example 4, except that instead of 5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepin[3', 4': 6,7]indolizino[1,2-b] quinoline-3,15(4H, 13H)-dione use 5,12-diethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4': 6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione. It is obtained as off white solid product, so pl. 238-239oC.

NMR1H (DMSO): of 0.82 (t, 3H); to 1.35 (t, 3H); for 2.01 (m, 2H); 2,85 (d, 2H); 3,18 (d, 2H); 3,22 (K, 2N); to 4.81 (s, 2H); 5,00 (sextet, 1H); of 5.24 (s, 2H); 5,78 (sextet, 1H); 7,38 (s, 1H); to 7.77 (t, 1H); 7,86 (t, 1H); 8,18 (d, 1H); of 8.28 (d, 1H); 12,10 (sextet, 1H).

NMR-FROM13(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; 145,59; 148,69; 152,62; 156,03; 161,22; 172,22.

Example 11: 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

11.A. 2-Ethyl-2-(2-methoxy-4-pyridyl)-1,3-dioxolane (F)

From a mixture of 2-chloro-4-propionylcarnitine (10 g, 59 mmol), obtained as O0 ml) distilled water (during the night) azeotropic method using nozzles Dean-stark. Then the solvent is removed under reduced pressure, the acid is neutralized with saturated aqueous sodium bicarbonate (100 ml) and the product extracted with diethyl ether. The combined ether extracts are washed with saturated saline solution, dried over sodium sulfate and evaporated, resulting in 13.3 g (96%) of crude product, protected by a carbonyl group, which is heated at the boil under reflux with 3 equivalents of sodium methoxide in acetonitrile until the end of the reaction (monitoring by thin layer chromatography: SiO2, tert-butyl-metaloxide/hexane (TBMA/CC, 50/50). After that, the combined acetonitrile solution is filtered and evaporated. The residue is dissolved in ether, washed with water and saturated saline solution, dried over sodium sulfate and evaporated, getting a brown oil which is distilled (70-75oWith, of 0.04 mbar), collecting 10.7 g (total yield 81%) of product (F) as a clear oil.

11.b. 2-Ethyl-2-(3-hydroxymethyl-2-methoxy-4-pyridyl)-1,3-dioxolane (G)

To a solution of bromoethylene (13 ml, 85 mmol) in anhydrous tetrahydrofuran (300 ml) at -78oWith under argon is added dropwise using a cannula tert-utility (1.7 M in pentane, 100 ml, 170 mmol). The obtained white precipitate is stirred actionnow the mixture is stirred for 15 minutes at -78oWith over one hour at 0oWith and for one hour at ambient temperature. After re-ohlazhdeniya to -78oWith added anhydrous N,N-dimethylformamide (100 ml) and the reaction mixture is left to warm to ambient temperature, then stirred for 16 hours, after which analysis by thin-layer chromatography (SiO2TBMO/Ledger from 50/50) shows that the original product is consumed completely. The reaction is stopped with saturated ammonium chloride and the reaction mixture extracted with diethyl ether (200 ml, 50 ml, 50 ml). The combined extracts dried over sodium sulfate and evaporated, receiving a yellow oil, which was purified column chromatography (SiO2TBMO/Ledger from 0/100 to 5/95, elwira derivatives meeteren, then from 20/80 to 50/50, elwira 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 (approximately 1 hour) with the analytical control by means of thin layer chromatography. Then the solvent is evaporated, the residue is dissolved in ether, washed with water and saturated salt solution is (total yield 62%) of product (G) as a yellow oil.

11.with. 2-(3-Benzoyloxymethyl-2-methoxy-4-pyridyl)-2-ethyl-1,3-dioxolane (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 (50 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 was kept at boiling under reflux for 16 hours. Then the reaction mixture is allowed to cool to ambient temperature, the reaction is stopped with water (50 ml) and the reaction mixture is concentrated under reduced pressure. The residue is dissolved in diethyl ether (150 ml), washed with water and saturated saline solution, dried and evaporated. Purification of column chromatography (SiO2TBMO/Ledger from 5/95 to 20/80) to give the product, 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) with a bath temperature of 120oC for 3 hours. The reaction mixture was concentrated under reduced pressure and the residual amount of acid neutralized by omatography (SiO2TBMO/CC, 10/90), which gives 5.5 g (70 %) of product (I).

11. E. tert-Butyl-ethyl--hydroxy--(3-benzoyloxymethyl-2-methoxy-4-pyridyl)propionate (J)

tert-Butylbromide (13 ml, 80 mmol) is added dropwise to a suspension of zinc (5.3 g, 80 mmol), activated 6 N. Hcl for 10 seconds, then washed sequentially with water to neutral reaction, acetone and diethyl ether, anhydrous tetrahydrofuran (60 ml) at boiling under reflux. Upon completion of the addition reaction medium is maintained at the boil under reflux for a further 10 minutes. Then add a solution of 1-(3-benzoyloxymethyl-2-methoxy-4-pyridyl)propane-1-she (5.8 g, 20 mmol) in anhydrous tetrahydrofuran (20 ml) and the reaction mixture is stirred at the boil under reflux for one hour. The reaction is stopped at 0oWith saturated aqueous ammonium chloride (100 ml) and the reaction mixture extracted with diethyl ether. The combined extracts dried over sodium sulfate and evaporated, giving a yellow oil, which was purified column chromatography (SiO2TBMO/Ledger from 5/95 to 10/90) to give tert-butyl ester (J) (7 g, 95%) as a clear liquid.

11. f. tert-Butyl--ethyl--hydroxy -(3-gidrol)propionate (1 g, 2.5 mmol) is subjected to hydrogenolysis at atmospheric pressure and at ambient temperature using a catalyst of 5% palladium on coal (50 mg) and absolute ethanol as solvent (10 ml). After completion of the reaction (6 hours), the catalyst was separated by filtration and the solvent is evaporated, giving 0.7 g (90%) of product (K) of sufficient purity for subsequent use synthetic.

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

tert-Butyl--ethyl--hydroxy--(3-hydroxymethyl-2-methoxy-4-pyridyl)propionate (8.6 g, 28 mmol) is treated triperoxonane acid (30 ml) for 3 hours at ambient temperature. Volatile components are evaporated and the residue purified column chromatography (SiO2CH2Cl2/MeOH from 100/0 to 98/2), which gives a clear oil, which after treatment with toluene leads to 5.9 g of product (L) (89%) as white crystals, so pl. 97-98oC.

11.h. 5-Ethyl-1,5-dihydro-5-hydroxyhexane[3,4-C]pyridine-3,9(4H,8H)-dione (M)

5-Ethyl-1,5-dihydro-5-hydroxy-9-methoxyacridine[3,4-C] pyridine-3(4H)-he (0.5 g, 2.1 mmol) is heated at the boil under reflux for 9 hours in 1 N. hydrochloric acid (20 ml). The reaction mixture is order overnight under reduced pressure in the presence of phosphorus pentoxide. The oil obtained is dissolved in anhydrous acetonitrile (5 ml) and stirred under argon for 24 hours. The precipitate is filtered off and dried, obtaining 0,23 g (49%) of white solid product (M), so pl. 118-119oC.

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

Use the method described Meth-Cohn and others, J. hm.Soc.Perkin Trans.I, p. 1520 (1981); Meth-Cohn, J. Chem.Soc. Perkin Trans.I, p.2509 (1981) and Nakasimhan etc., J. Am.Chem.Soc., 112, R. 4431 (1990). 3,4-Etilendioksitiofenom (22 g, 113 mmol) is added to the reagent Vilsmeier obtained by adding dropwise phosphorus oxychloride (71 ml, 0.77 mol) to the anhydrous dimethylformamide (23 ml, 0.28 mol), cooled in a bath of ice/water and again stirred for 0.5 hour in an argon atmosphere. The resulting mixture is heated at 75oC for 16 hours. After cooling to ambient temperature the reaction mixture was added into a mixture of ice and water (300 ml) and extracted with dichloromethane (I ml). The combined organic extracts dried over sodium sulfate, filtered and concentrated. The solid residue is suspended in dichloromethane (20 ml) filtered and dried under reduced pressure, giving 10 g (35%) of 2-chloro-6,7-ethylenedioxythiophene-3-carbaldehyde as a yellow solid, so pl. 222-224oC. This intermediate SOE ml) by boiling under reflux for 24 hours. After cooling to ambient temperature the solvent is removed under reduced pressure and the residue is placed in water 50% tetrahydrofuran (200 ml), filtered, washed with tetrahydrofuran and dried under reduced pressure to yield 12 g of 6,7-Ethylenedioxy-2-eothinon-3-carbaldehyde as a yellow solid, so pl. 155-157oC. the Above intermediate compound is treated with sodium borohydride (2 g, 52 mmol) in methanol (200 ml) at ambient temperature for 0.5 hours. The solvent is removed under reduced pressure, the residue is placed in water and filtered. The obtained solid is dried under reduced pressure in the presence of phosphorus pentoxide, giving 11 g (6,7-Ethylenedioxy-2-eothinon-3-yl)methanol as a yellow solid product, so pl. 178-180oC.

11. j. 5-Ethyl-8-(6,7-Ethylenedioxy-2-iodine-3-rhinoliner)-1,5-dihydro-5-hydroxy-oxepin[3,4-C]pyridine-3,9(4H,8H)-dione (ABOUT)

Diethylazodicarboxylate (570 μl, 3.6 mmol) was added dropwise during 5 minutes 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 preceding 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./reaktsionnuyu the mixture is concentrated under reduced pressure and the residue is dissolved in chloroform (100 ml). The resulting solution was washed with brine (4x50 ml), dried over sodium sulfate and evaporated. The residue is purified column chromatography (SiO2CH2Cl2/MeOH, 99/1 to 98/2) that give 650 mg (66% of the product (About) 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 bromide (352 mg, 1.1 mmol), sodium acetate (359 mg, 4.4 mmol) and palladium (II) acetate (98 mg, 0.43 mmol) dissolved in anhydrous acetonitrile (40 ml) and heated at 90oWith argon 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 over phosphorous pentoxide, giving 250 mg of the target compound as a pale yellow solid product, so pl. >250oC.

NMR1H (DMSO): of 0.91 (t, 3H); to 1.87 (m, 2H); is 3.08 (d, 1H); 3,51 (d, 1H); of 4.45 (s, 4H); 5,19 (s, 2H); vs. 5.47 (DD, 2H); 6,02 (sextet, 1H); 7,33 (s, 1H); rate of 7.54 (s, 1H); at 7.55 (s, 1H); 8,43 (s, 1H).

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 compound is obtained by the method similar to that specified in stage 11.i. example 11, but using 4-benzyloxyaniline instead of 3,4-etilendioksitiofenom. Purification by chromatography on a column of silica gel, using dichloromethane as the eluent required for the isolation of intermediate 6-benzyloxy-2-chlorhydrin-3-carbaldehyde, so pl. 180-182oWith (yield 8%) of sufficient purity. Then the exchange of the halogen gives 6-benzyloxy-2-eothinon-3-carbaldehyde, so pl. 155-157oWith, and subsequent recovery with sodium borohydride gives (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 compound is obtained by the method similar to that specified 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. This compound exists in the form of a white solid product, so pl. 197-199oC.

12.with. 10-Benzyloxy-5-ethyl-4,5-dihydro-5-tech indicated 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 obtained as light-yellow solid product. so pl.>250oC.

NMR1H (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); 6,05 (c, 1H); 7,30-of 7.70 (m, 8H); 8,10 (d, 1H); 8,55 (c, 1H).

NMR-FROM13(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.

Example 13: -(12-benzyloxy-8-hydroxymethyl-9-oxo-(11N)-indolizino[1,2-b]quinoline-7-yl)--ethyl--hydroxypropionic acid (E)

This compound is obtained by the method similar to that specified 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. Get a connection in the form of a yellow solid product, so pl. 171-173oC.

NMR1H (DMSO): to 0.80 (t, 3H); 2,00 (m, 2H); 2,85 (d, 1H); 3.15 in (d, 1H); 4.80 to (s, 2H); 5.25 in (s, 2H); and 5.30 (s, 2H); 5,75 (sextet, 1H); 7,30 (s, 1H); 7,35 - 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 ambient temperature, using as catalyst 10% palladium on coal (60 mg) and triperoxonane acid (15 ml) as solvent. After 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 components are evaporated under reduced pressure, the resulting crude target product containing trace amounts triperoxonane acid. These trace amounts are removed joint distilled 1,4-dioxane. The product is obtained as an orange solid substance, so pl. 150oC (decomp.), sufficient purity for subsequent use synthetic.

NMR1H (DMSO): to 0.89 (t, 3H); 1.85 to (K, 2N); to 3.02 (d, 1H); of 3.45 (d, 1H); 5,19 (c, 2H); lower than the 5.37 (d, 1H); of 5.50 (d, 1H); 5,98 (sextet, 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).

NMR-FROM13(DMSO): of 8.47;metilamino)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

15. A. 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

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 an aqueous 37% formaldehyde (500 μl) and aqueous 40% dimethylamine (500 μl) and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture is concentrated to dryness and the residue purified column chromatography (SiO2CH2Cl2/MeOH from 100/0 to 90/10) followed by crystallization from acetonitrile, giving 102 mg of the target compound.

15. b. Hydrochloride 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

Diluted hydrochloric acid (1 BC) was 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 (102 mg) in water until dissolved. The water is evaporated under reduced pressure and the residue suspended in acetonitrile (5 ml) and filtered, giving 103 mg of the target salt, so pl. 248oC (decomp.).

NMR1H (DMSO): 0,88 (t, 3H); of 1.85 (m, 2H); 2,84 (C, 6N); 3, is).

NMR-FROM13(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-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

This compound is obtained from 3-fluoro-4-methoxyaniline in accordance with the method illustrated in stages 11i, 11j and 11k of example 11, in the form of a yellow solid product, so pl.>250oC.

NMR1H (DMSO): to 0.89 (t, 3H); 1.85 to (K, 2N); is 3.08 (d, 1H); 3,49 (d, 1H); 4,00 (s, 3H); 5.25 in (s, 2H); of 5.39 (d, 1H); 5,51 (d, 1H); 6,00 (s, 1H); to 7.32 (s, 1H); 7,72 (d, 1H); to $ 7.91 (d, 1H); 8,58 (s, 1H).

NMR-FROM13(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; 155,81; 159,20; 172,06.

IR (KBr): 1259; 1503; 1602; 1737.

Example 17: 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

This compound is obtained from 3-chloro-4-methoxyaniline in accordance with the method illustrated in stages 11i, 11j and 11k of example 11, in the form of a yellow solid product, so pl.>250oC.

NMR1H (DMSO): of 0.85 (t, 3H); 1.85 to (K, 2N); to 2.55 (s, 3H); of 3.07 (d, 1H); of 3.45 (d, 1H); 5.25 in (s, 2H); of 5.39 (d, 1H); 5,51 (d, 1H); 6,05 (s, 1H); 7,39 (s, 1H); 8,10 (s, 1H); to 8.20 (s, 1H); at 8.60 (s, 1H).

NMR-FROM13(DMSO): 8,43; 20,20; 606; 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, 3H)-dione.

This compound is obtained from 3,4-diptiranjan in accordance with the method illustrated in stages 11i, 11j and 11k of example 11, in the form of a yellow solid product, so pl.>250oC.

NMR1H (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); of 5.39 (d, 1H); 5,51 (d, 1H); 6,05 (s, 1H); 7,39 (s, 1H); 8,15 (K, 1H); 8,25 (K, 1H); 8,68 (s, 1H).

NMR-FROM13(DMSO): 8,41; 36,45; 42,48; 50,68; 61,40; 73,25; 99,92; 114,44; 115,42; 115,58; 122,96; 125,52; 130,56; 131,46; 144,21; 145,25; 142,36; 153,41; 155,85; 159,15; 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[1,2-b]quinoline-9,12(14N)-dione

This compound is obtained from 3,4-methylenedioxyaniline in accordance with the method illustrated in stages 11i, 11j and 11k of example 11, in the form of a solid cream color, so pl.>250oC.

NMR1H (DMSO): of 0.85 (t, 3H); 1.85 to (K, 2N); of 3.07 (d, 1H); of 3.45 (d, 1H); 5,20 (s, 2H); of 5.39 (d, 1H); 5,51 (d, 1H); 6,00 (c, 1H); 6.30-in (s, 2H); 7,30 (c, 1H); 7,49 (d, 2H); to 8.45 (s, 1H).

NMR-FROM13(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; 17H,13H)-dione

This compound is obtained from 3-chloro-4-methoxyaniline in accordance with the method illustrated in stages 11i, 11j and 11k of example 11, in the form of a white solid product, so pl.>250oC.

NMR1H (DMSO): of 0.85 (t, 3H); 1.85 to (K, 2N); of 3.07 (d, 1H); of 3.45 (d, 1H); 4,01 (c, 3H); 5,22 (c, 2H); of 5.39 (d, 1H); 5,51 (d, 1H); of 6.02 (s, 1H); 7,31 (s, 1H); 7,68 (s,1H); to 8.20 (s, 1H); 8,55 (s, 1H).

NMR-FROM13(DMSO): 8,22; 36,27; 42,30; 50,48; 56,69; 61,23; 73,08; 99,16; 107,44; 122,16; 127,12; 128,12; 129,25; 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 in accordance with the method illustrated in stages 11.i., 11.j. and 11.k. example 11 in the form of a yellow solid product, so pl.>250oC.

NMR1H (DMSO): of 0.85 (t, 3H); 1.85 to (K, 2N); of 3.07 (d, 1H); of 3.45 (d, 1H); of 3.95 (s, 3H); 5,28 (s, 2H); of 5.40 (d, 1H); 5,51 (d, 1H); 6,00 (s, 1H); 7,38 (s, 1H); 7,51 (d,2H); 8,07 (d, 1H); 8,55 (s, 1H).

NMR-FROM13(DMSO): 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

11.k. example 11 in the form of a yellow solid product, so pl.>250oC.

NMR1H (DMSO): of 0.85 (t, 3H); 1.85 to (K, 2N); of 3.07 (d, 1H); of 3.45 (d, 1H); and 5.30 (s, 2H); 5,41 (d, 1H); of 5.55 (d, 1H); between 6.08 (s, 1H); 7,41 (s, 1H); with 8.05 (s, 1H); 8,21 (s, 1H); 8,91 (s, 1H).

NMR-FROM13(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 in accordance with the method illustrated in stages 11.i, 11.j and 11.k. example 11 in the form of a yellow solid product, so pl.>250oC.

NMR1H (DMSO): to 0.89 (t, 3H); 1.85 to (K, 2N); 2,49 (s, 3H); is 3.08 (d, 1H); 3,49 (d, 1H); to 5.21 (s, 2H); of 5.39 (d, 1H); 5,51 (d, 1H); 6,05 (s, 1H); 7,39 (s, 1H); 7,87 (d, 1H); with 8.05 (d, 1H); 8,61 (s, 1H).

NMR-FROM13(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; 172,02.

IR (KBR): 1054; 1580; 1651; 1760.

Example 24: 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

This compound is obtained from 4-foronline in accordance with the method illustrated in stages 11.i., 11.j. and 11.k. example 11, in the form of a white is with, 2H); of 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).

NMR-FROM13(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 in accordance with the method illustrated in stages 11.i., 11.j. and 11.k example 11, in the form of a yellow solid product, so pl.>250oC.

NMR1H (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); of 5.39 (d, 1H); 5,51 (d, 1H); 6,05 (s, 1H); 7,39 (s, 1H); 7,89 (d, 1H); 8,19 (d, 1H); 8,29 (s, 1H); 8,67 (s, 1H).

NMR-FROM13(DMSO): 8,40; 36,46; 42,47; 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: 9-chloro-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

This compound is obtained from 4-chloro-3-foronline in accordance with the method illustrated in stages 11.i., 11.j. and ll.k. example 11 in the form of a yellow solid product, so pl.>250oC.

NMR1H (DMSO): of 0.85 (t, 3H); 1.85 to (K, 2N); of 3.07 (d, 1H); of 3.45 (d, 1H); 5.25 in (c, 2H); of 5.39 (d, 1H); 5,51 (d, 1H); 6,05 (s, 1H); 7,40 (s, 1H),31; 144,13; 145,08; 153,57; 154,13; 155,84; 156,61; 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 in accordance with the method illustrated in example 15. A. in the form of a white solid product, so pl. >250oC.

NMR1H (DMSO): of 0.85 (t, 3H); 1,87 (K, 2N); 2,53 (s, 4H); 3,03 (d, 1H); of 3.45 (d, 1H); was 4.02 (s, 2H); free 5.01 (s, 2H); 5,38 (d, 1H); 5,52 (d, 1H); 6,00 (sextet, 1H); 7,30 (s, 1H); 7,42 (d, 1H); to 7.95 (d, 1H); 8,82 (s, 1H).

NMR-FROM13(DMSO): 8,45; 36,49; 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)-dione

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

This product is obtained according to T. Sugasawa, T. Toyoda, M. Adachi, K. Sasakura, J. Am.Chem.Soc., 100 (1978), R. 4842-4852. Trichloride boron (1M in heptane, 156 ml, 156 mmol) at 0oC in an atmosphere of argon is added dropwise to a solution of 3-fluoro - 4-methoxyaniline (20 g, 142 mmol) in anhydrous dichloromethane (200 ml). Thus obtained pink, the suspension is incubated under stirring for 5 minutes, then add the ol). The reaction mixture is heated at the boil under reflux for 3 hours, cooled to 0oWith, hydrolyzing, carefully adding 2 N. hydrochloric acid (100 ml), then refluxed for 45 minutes. After cooling to 0oWith the obtained precipitate is filtered off, washed with dichloromethane, then placed in water (300 ml). The aqueous phase is alkalinized to alkaline pH, extracted with dichloromethane and then ethyl acetate. The organic phase is dried (MgSO4), and then evaporated, to give crude product, which was purified column chromatography (SiO2, AcOEt/heptane, from 1/99 to 20/80). Gain of 15.3 g of the yellow solid product.

NMR1H (CDCl3): of 1.20 (t, 3H); 2,92 (K, 2N); a 3.83 (s, 3H); 6,2 (s, 2H); 6,40 (d, 2H); to 7.32 (d, 2H).

IR (KBR): 857; 1148; 1240; 1561; 1583; 1662.

28.b. Ethyl-4-ethyl-7-fluoro-2-hydroxy-6-methoxy-3-chinainternational

The solution of chloride ethylmalonyl (12.9 ml, 100 mmol) in anhydrous acetonitrile (30 ml) is added dropwise in argon at 0oTo 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). The reaction mixture is left to warm to ambient temperature, dropwise via cannula in argon dobavliaut for 12 hours at ambient temperature. The reaction mixture was poured into ice water (100 ml) and stirred for two hours, then the precipitate is filtered off and washed with water, ethanol and ether. Get to 19.4 g of a white solid product.

NMR1H (DMSO): 1,25 (m, 6N); 2,78 (K, 2N); to 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.with. 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 at boiling under reflux for 6 hours. Phosphorylchloride distilled off. The reaction mixture is decanted into ice water, then placed in dichloromethane to dissolve. The organic phase is washed with water, then saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is evaporated. The residue is suspended in ether and unreacted source product (4 g) is filtered off. The filtrate is evaporated and the residue purified column chromatography (SiO2, AcOEt/heptane, from 5/95 to 20/80). Get to 10.9 g of white solid product.

NMR1H (DMSO): of 1.30 (t, 3H); 1.39 in (t, 3H); is 3.08 (K, 2H); 4.09 to (s, 3H); 4,49 (K, 2N); to 7.64 (d, 2H); 7,86 (d, 2H).

oC for 4 hours. After cooling to 0oWith carefully add 20% aqueous solution of salt of Rochelle (Rochelle) (105 ml) and dichloromethane (200 ml) and the reaction mixture was kept under stirring for 1 hour, then decanted and washed three times with water. The organic phase is dried over magnesium sulfate and the solvent is evaporated. The residue is purified column chromatography (SiO2, AcOEt/heptane, from 5/95 to 50/50). Get 6 g of white solid product.

NMR1H (DMSO): of 1.28 (t, 3H); 3.25 to (K, 2N); Android 4.04 (s, 3H); of 4.77 (d, 2H); at 5.27 (t, 1H); at 7.55 (d, 2H); 7,73 (d, 2H).

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

28. that is, 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

Spend the interaction of 2-chloro-4-ethyl-7-fluoro-6-methoxy-3-kinalimutan with compound (M) as described in stage 11.j. example 11. The resulting product cyclist in accordance with the method described in stage 11.k. Receives a yellow solid product, so pl.>275oC.

NMR-FROM13(CF3COOD): 9,03; 14,20; 26,68; 38,77; 43,98; 53,79; 58,27; 64,73; 77,93; 106,85; 109,24; 110,15; 128,99; 129,20; 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

The method described in examples 28.b., 28.with. and 28.d., used for 2-acetanilide to obtain 2-chloro-4-methyl-3-kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl.>260oC.

NMR1H (DMSO): of 0.87 (t, 3H); 1,87 (K, 2N); 2,78 (s, 3H); 2,80 (d, 1H); 3,55 (d, 1H); at 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).

NMR-FROM13(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; 159,09; 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 to T. Sugasawa, T is onitrile (11,4 ml, 180 mmol) and the molar chloride solution diethylamine in hexane (164 ml, 164 mmol) are sequentially added dropwise in an inert atmosphere at 0oTo a solution of 3-chloro-4-methoxyaniline (23,6 g, 150 mmol). The reaction mixture is heated at the boil under reflux for 1 hour, cooled to 0oWith hydrolift careful addition of 2 N. hydrochloric acid (90 ml), then refluxed for 1 hour. The reaction mixture is cooled and added a concentrated solution of soda ash to a pH of 14. The extraction is carried out with ethyl acetate, the organic phase is washed with water, then with salt water. Next, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is placed in isopentane, followed by decantation, then nerastvorim part is placed in a minimum amount of isopropyl ether, add I-pentane to precipitate the product, and then filtered and dried in vacuum. Get 17,26 g of a brown solid product.

NMR1H (CDCl3): is 3.82 (s, 3H); 4,60 (s, 2H); 6,11 (s, 2H); is 6.78 (s, 1H); 7,11 (s, 1H).

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

The solution of chloride ethylmalonyl (17 ml, 131 mmol) is added dropwise in argon at 0ois nitrile (310 ml). Conduct stirring for 2 hours at ambient temperature, then added dropwise at 0oWith the solution ethanolate sodium in ethanol (obtained from 1.88 g, 80 mmol of sodium in 90 ml of ethanol). Conduct stirring for 12 hours at ambient temperature, add 300 ml of water and again stirred for 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 product.

NMR1H (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-dichloro-4-chloromethyl-6-methoxy-3-chinainternational

A suspension of ethyl-7-chloro-4-chloromethyl-2-hydroxy-6-methoxy-3-chinainternational (of 116.7 g, 50 mmol) in phosphorylchloride (100 ml) is heated at boiling under reflux for 6 hours. Phosphorylchloride distilled off. The residue is placed in water and stirred for 30 minutes. The precipitate is filtered off and washed with water until neutral. The residue is placed in dichloromethane and washed with a saturated solution of sodium chloride. After filtration through a layer of celite the filtrate is decanted. The organic phase is washed repeatedly with a saturated solution of sodium chloride, then dried over Sul is P-1H (CDCl3): of 1.47 (t, 3H); 4,08 (t, 3H); 4,55 (K, 2N); to 4.87 (s, 2H); to 7.35 (s, 1H); of 8.09 (s, 1H).

30. d. Ethyl-2,7-dichloro-6-methoxy-4-(4-methylpiperazine)-3-chinainternational

A mixture of ethyl-2,7-dichloro-4-chloromethyl-6-methoxy-3-chinainternational (6.9 g, 20 mmol) and N-methylpiperazine (9 ml, 80 mmol) is heated at 60oC for 30 minutes. The reaction mass is diluted with water and carry out the extraction with ethyl acetate. After desantirovaniya the organic phase is washed with water, then dried over magnesium sulfate, filtered and evaporated in vacuum. The residue is placed in water, stirred for 15 minutes, filtered, washed with water and dried in vacuum. The residue is purified column chromatography (SiO2, MeOH/CH2Cl2from 5/95 to 8/92). Obtain 6.7 g of the product as beige solid.

NMR1H (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-Dichloro-6-methoxy-4-(4-methylpiperazine)-3-kinalimutan.

Ethyl-2,7-dichloro-6-methoxy-4-(4-methylpiperazine)-3-chinainternational (6 g, 14.5 mmol) was dissolved in methylene chloride (120 ml). Slowly add molar solution of diisobutylaluminium in methylene chloride (60 ml, 60 mmol). Stirred techinial Rochelle. Stirred for one hour, then filtered through celite and decanted; the organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The solid is placed in isopropyl ether, filtered and dried in vacuum. Obtain 4.3 g of the desired product (80%) as a yellow solid.

NMR1H (CDCl3): of 2.27 (s, 3H); 2,30 is 2.80 (m, 8H); a 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

Spend the interaction of 2,7-dichloro-6-methoxy-4-(4-methylpiperazine)-3-kinalimutan with compound (M) as described in stage 11.j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl.>250oC.

NMR1H (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 (c, 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).

NMR-FROM13(DMSO): 8,42; 36,53; 50,65; 53,30; 56,67; 62,00; 66,50; 73,32; 99,31; 104,86; 122,32; 126,94; 127,70; 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; 1�isino[1,2-b]quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., used for 3-chloro-4-methoxyaniline to obtain ethyl-2,7-dichloro-4-chloromethyl-6-methoxy-3-chinainternational, which is treated by the method of example 30.d., using morpholine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11. The resulting product cyclist in accordance with method stage 11.k. Get a beige solid product, so pl.> 250oC.

NMR1H (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 and (C, 1H).

NMR-FROM13(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; 153,10; 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-methylpiperazine)-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., apply for aniline order to obtain ethyl-2-chloro-4-chloromethyl-3-chinainternational, which is treated in accordance with the act is adequate kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl.> 260oC.

NMR1H (DMSO): 0,86 (t, 3H); 1,87 (K, 2N); and 2.14 (s, 3H); 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 (sextet, 1H); 7,40 (s, 1H); 7,72 (t, 1H); a 7.85 (t, 1H); is 8.16 (d, 1H); to 8.45 (d, 1H).

IR (KBr): 1652; 1735; 3424.

Example 33: 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

The method described in examples 30.A., 30.b. and 30.S., apply for aniline order to obtain ethyl-2-chloro-4-chloromethyl-3-chinainternational, which is treated in accordance with the method of example 30.d. using piperidine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j. example 11. Received ultimately leading product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl.> 260oC.

NMR1H (DMSO): 0,86 (t, 3H); of 1.40 (sextet, 2H); to 1.48 (sextet, 4H); 1,87 (K, 2N); 2,50 (s, 4H); 3,05 /P>NMR-FROM13(DMSO): 8,47; 23,50; 25,82; 36,50; 42,50; 50,68; 54,57; 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-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., apply for aniline order to obtain ethyl-2-chloro-4-chloromethyl-3-chinainternational, which is treated by the method of example 30.d., using morpholine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl.> 260oC.

NMR1H (DMSO): 0,86 (t, 3H); 1,87 (K, 2N); 3,05 (d, 1H); 3,30 (s, 4H); 3,49 (d, 1H); 3,55 (sextet, 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); 8,16 (d, 1H); of 8.47 (d, 1H).

NMR-FROM13(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-methylpiperazin used for 4-foronline order to obtain ethyl-2-chloro-4-chloromethyl-6-fluoro-3-chinainternational, which is treated according to the method of example 30.d. N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl.> 275oC.

NMR1H (DMSO): of 0.87 (t, 3H); 1.85 to (K, 2N); of 2.15 (s, 3H); 2,31 (m, 4H); 2.50 each (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); 6,05 (s, 1H); 7,38 (s, 1H); to 7.77 (m, 1H); 8,19 (m, 2H).

NMR-FROM13(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

The method described in examples 30.A., 30.b. and 30.S., used for 4-foronline order to obtain ethyl-2-chloro-4-chloromethyl-6-fluoro-3-chinainternational, which is treated by the method of example 30.d., using morpholine instead of N-methylpiperazine, then restore in accordance with the method of example 30. that is, in the appropriate kinalimutan. The latter is subjected to interaction with siposova stage 11. k. Get a beige solid product, so pl.> 250oC.

NMR1H (DMSO): 0.87 (m, 3H); of 1.85 (m, 2H); of 2.51 (m, 4H); a 3.06 (d, 1H); 3,48 (d, 1H); of 3.56 (m, 4H); of 4.05 (m, 2H); of 5.34 (s, 2H); of 5.40 (d, 1H); of 5.53 (d, 1H); 6,04 (s, 1H); 7,38 (s, 1H); to 7.77 (m, 1H); 8,21 (m, 2H).

NMR-FROM13(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

The method described in examples 30. and, 30.b. and 30.S., used for 3-fluoro-4-methylaniline to obtain ethyl-2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-chinainternational, which is treated by the method of example 30.d. N-methylpiperazine, then restore in accordance with the method of example 30. that is, in the appropriate kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl.> 250oC.

NMR1H (CDCl3): and 1.00 (t, 3H); 2,00 (K, 2N); to 2.35 (s, 3H); 2.50 each (s, 3H); 2,61 (m, 8H); to 3.33 (d, 1H); 3,39 (d, 1H) ; of 3.97 (d, 1H); 4,07 (d, 1H); 5.17 to (on the Il-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

The method described in examples 30.A., 30.b. and 30.S., used for 3-fluoro-4-methylaniline to obtain ethyl-2 - chloro-4-chloromethyl-7-fluoro-6-methyl-3-chinainternational, which is treated by the method of example 30.d., using morpholine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl.> 260oC.

NMR1H (DMSO+Dl3): and 1.00 (t, 3H); 2,02 (K, 2N) ; to 2.57 (s, 3H); 2,60 (s, 4H); 3,23 (D, 1H); of 3.45 (d, 1H) ; of 3.75 (s, 4H); 4,11 (s, 2H); 5,44 (s, 1H); vs. 5.47 (d, 1H); the 5.65 (d, 1H); a 7.62 (s, 1H); 7,73 (d, 1H); 8,24 (d, 1H).

NMR-FROM13(CF3CO2D): 8,35; 13,93; 16,01; 22,24; 25,29; 38,18; 43,42; 54,19; 56,04; 56,74; 64,16; 65,09; 77,48; 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

The method described in examples 30.A., 30.b. and 30.S., used for 3-fluoro-4-methylaniline to obtain ethyl-2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinoline is m restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl.> 260oC.

NMR1H (CF3CO2D): 1,09 (s, 3H); 1.70 to (t, 1H); 2,03 (m, 5H); 2,25 (s, 2H); 2,70 (s, 3H); 3,54 (d, 3H); 3,88 (d, 1H); 4,01 (sextet, 2H); 5,30 (K, 2N); the 5.65 (d, 1H); 5,96 (d, 1H); 6,10 (s, 2H); is 8.16 (d, 1H); 8,35 (s, 1H); 8,61 (s, 1H).

NMR-FROM13(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; 1657; 1728; 3399.

Example 40: 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(15 NM)-dione

The method described in examples 30.A., 30.b. and 30.S., apply for 3,4-metilendioxifenil order to obtain ethyl-2-chloro-4-chloromethyl-6,7-Ethylenedioxy-3-chinainternational, which is treated by the method of example 30.a. N-methylpiperazine, then restore in accordance with the method of example 30. that is, in the appropriate kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j. example 11.the product, so pl.> 260oC.

NMR1H (DMSO): to 0.92 (t, 3H); 1,89 (K, 2N); of 2.16 (s, 3H); 2.50 each (m, 8H); 3,12 (d, 1H); 3,50 (d, 1H); 3,95 (c, 2H) ; 4,47 (s, 4H); 5,19 (K, 2N); 5,43 (d, 1H); to 5.56 (d, 1H); to 7.35 (s, 1H); rate of 7.54 (s, 1H); 7,76 (s, 1H).

NMR-FROM13(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; 155,99; 159,18; 172,27; 177,00.

IR (KBr): 1656; 1743; 3422.

Example 41: 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

The method described in examples 30.A., 30.b. and 30.S., used for 3-chloro-4-foronline order to obtain ethyl-2,7-dichloro-4-chloromethyl-6-fluoro-3-chinainternational, which is treated by the method of example 30.d., using morpholine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11. The resulting product cyclist in accordance with method stage 11.k. Get a beige solid product, so pl.> 250oC.

NMR1H (CF3D): 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, 1H); 5,64 (d, 1H); 5,96 (d, 1H); 6,23 (K, 2N); to 8.57 (d, 1H); at 8.60 (s, 1H); cent to 8.85 (d, 1H).

IR (KBr): 848; 1042; 1230; 1609; 1658; 1750; 3310; 3387.

Example 42: division 5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepin[3',4': 6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

A mixture of ethyl--hydroxy-(8-hydroxymethylcytosine[1,2-b] quinoline-9-(11N-he-7-yl)propionic acid (19.5 g, 51 mmol) and L-(-) - methylbenzylamine (12,12 g, 100 mmol) in absolute ethanol (1 l) was heated to boiling, followed by filtration in the form of heat and leave for 68 hours. The precipitate is filtered and washed with ethanol and ether, receiving of 9.8 g of white solid product. Analysis using liquid chromatography high pressure on chiral stationary phase ("Chiral HPLC on the column "Chiral-AGP (Chromtech, Stockholm, Sweden) h mm, eluent 2% acetonitrile in 10 mm phosphate buffer at pH 6.9, the peaks suiryudan at 4.5 and 7.5 minutes) reveals two peaks, integrated respectively as 24% and 76% of the total area of the two peaks. The solid is dissolved in 93% ethanol (350 ml) by boiling under reflux, then leave for 48 hours. The precipitate is filtered off, then washed with ethanol and ether, receiving 4.8 g of a solid white product, which gives two peaks, integrable respectively 9% and 91% of the total area of the two peaks, using chiral HPLC. Solid substance p is live, then washed with ethanol and ether to obtain 2.7 g of a solid white product, which gives two peaks, integrable respectively as 3% and 97% of the total area of the two peaks, using chiral HPLC. The solid is dissolved in 50% ethanol (22 ml) by boiling under reflux and leave for 48 hours. The precipitate is filtered off, then washed with ethanol and ether, obtaining 1.6 g white solid product, which gives two peaks, integrable respectively at 1% and 99% of the total area of the two peaks, using chiral HPLC. Received diastereomeric enriched salt dissolved in distilled water (20 ml), treated with 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 80oTo obtain 1.1 g of white solid product. The latter is dissolved in absolute ethanol (55 ml) with added concentrated hydrochloric acid (11,5 N., 11 ml) to give a yellow solution, which is kept under stirring at ambient temperature for 68 hours. Thus obtained precipitate is filtered and washed with water, ethanol and ether, then dried in vacuum at 80oSince getting it. Analysis by chiral HPLC (column Chiral-AGP, elution gradient from 2% to 5% acetonitrile in 10 mm phosphate buffer at pH 6.9, the peaks suiryudan at 15 and 20 minutes) shows the enantiomeric excess of 98%. The above-described method is repeated, substituting 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.

Example 43: hydrochloride 5-ethyl-9,10-debtor-4,5-dihydro-5-hydroxy-12-(1,2,5,6-tetrahydropyridine-1H-oxepin [3', 4':6,7] indolizino[1,2-b] quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., apply for 3,4-diferencia order to obtain ethyl-2-chloro-4-chloromethyl-6,7-debtor-3-chinainternational, which is treated by the method of example 30.d. using 1,2,5,6-tetrahydropyridine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11. The resulting product cyclist in accordance with method stage 11.k. Thus obtained free base is suspended in absolute ethanol (50 ml/mmol), the ATEM after concentrating the solution to 40% of its original volume precipitation, which is collected by filtration and washed with ether. Get a light orange solid product, so pl. 264oC.

NMR1H (DMSO): of 0.87 (t, 3H); 1.85 to (K, 2N); and 2.26-of 2.30 (m, 1H); 2.50 each (m, 1H); to 3.09 (d, 1H); 3.40 in (m, 2H); 3,48 (d, 1H); a 3.87 (m, 4H); of 5.05 (m, 1H); 5,48 (K, 2N); the 5.65 (m, 2H); of 5.89 (m, 1H); 7,42 (s, 1H); 8,24-8,30 (m, 1H); 8,76-8,82 (m, 1H); 10,86 (s, 1H).

NMR-FROM13(DMSO): 8,44; 22,36; 36,5; 42,7; 48,71; 50,30; 51,49; 61,42; 73,23; 100,16; 112,64; 112,83; 116,05; 120,26; 123,31; 125,29; 125,40; 131,17; 133,97; 144,15; 146,26; 146,37; 148,74; 150,52; 151,23; 153,20; 153,53; 155,99; 159,04; 172,02.

IR (KBr): 662; 1064; 1268; 1452; 1523; 1598; 1652; 1743; 2936; 3027; 3418.

Example 44: 5-ethyl-9,10-debtor-4,5-dihydro-5-hydroxy-12-(4-methylpiperidino)-1H-oxepin[3', 4': 6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., apply for 3,4-diferencia order to obtain ethyl-2-chloro-4-chloromethyl-6,7-debtor-3-chinainternational, which is treated by the method of example 30.d., using 4-methylpiperidin instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j. example 11. The resulting product cyclist in accordance with method stage 11.k. Get a beige solid product, so pl.> 250<4 (, 2H); 5,3 (s, 2H); of 5.45 (DD, 1H); 6,05 (s, 1H); to 7.35 (s, 1H); 8,15 (DD, 1H); to 8.45 (DD, 1H).

IR (KBR): 1454; 1518; 1608; 1668; 1733; 2804; 2926; 3311.

The suspension of the above free base in absolute ethanol (50 ml/mmol) with subsequent treatment of ethanolic hydrogen chloride (2,5 N. , 5 EQ.) allows you to obtain the corresponding hydrochloride. Initially formed yellow solution, and then the precipitate, which is collected by filtration after concentration to 40% of the initial volume, and then washed with ether. Get a bright orange solid product, so pl.> 250oC.

NMR1H (DMSO): 0,85 (m, 6N); and 1.7 (m, 5H); 1,85 (K, 2H); 3.15 in (s, 1H); of 3.25 (DD, 2H); 3,3 (m, 2H) and 4.9 (s, 2H); of 5.45 (DD, 2H); 5,6 (s, 2H); 6,1 (s, 1H); to 7.4 (s, 1H); of 8.25 (DD, 1H); is 8.75 (DD, 1H); 10,35 (s, 1H).

IR (KBR): 1270; 1455; 1523; 1606; 1653; 1742; 2943; 3419.

Example 45: 5-ethyl-9,10-debtor-4,5-dihydro-5-hydroxy-12-pyrrolidinyl-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., apply for 3,4-diferencia order to obtain ethyl-2-chloro-4-chloromethyl-6,7-debtor-3-chinainternational, which is treated by the method of example 30.d., using pyrrolidine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in southwest 11. The resulting product cyclist in accordance with method stage 11.k. Get a beige solid product, so pl.> 250oC.

NMR1H (DMSO): of 0.85 (t, 3H); 1,7 (s, 4H); 1.85 to (K, 2N); to 2.55 (s, 4H); of 3.25 (DD, 2H); 4,15 (d, 2H); to 5.35 (s, 2H) ; of 5.45 (DD, 2H); 6,05 (s, 1H); to 7.35 (s, 1H); 8,15 (DD, 1H); to 8.45 (DD, 1H).

IR (KBR): 1455; 1518; 1605; 1657; 1731; 2801; 2970; 3422.

The suspension of the above free base in absolute ethanol (50 ml/mmol) with subsequent treatment of ethanolic hydrogen chloride (2,5 N. , 5 EQ.) allows you to obtain the corresponding hydrochloride. Initially formed yellow solution, and then the precipitate, which is collected by filtration after concentration to 40% of the initial volume, and then washed with ether. Get a light orange solid product, so pl.> 250oC.

NMR1H (DMSO): of 0.85 (t, 3H); 1,9 (m, 4H); 2,1 (s, 2H); of 3.25 (DD, 2H); 3,3 (m, 2H); 3,55 (m, 2H); of 5.05 (s, 2H); of 5.45 (DD, 2H); 5,6 (s, 2H); 6,1 (s, 1H); to 7.4 (s, 1H); 8.3 (the DD, 1H); is 8.75 (DD, 1H); 10,75 (c, 1H).

IR (KBR): 1454; 1522; 1603; 1653; 1743; 2970; 3394.

Example 46: 5-ethyl-9,10-debtor-4,5-dihydro-5-hydroxy-12-(4-methylpiperazine-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., apply for 3,4-diferencia order to obtain the 4-methylpiperidin instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl.> 250oC.

NMR1H (CDCl3+CD3OD): 0,99 (t, 3H); 2,00 (K, 2N); 2,32 (s, 3H); 3.24 in (d, 1H); 3,37 (s, 1H); 3.42 points (d, 1H); Android 4.04 (s, 2H); lower than the 5.37 (s, 2H); 5,43 (d, 1H); 5,64 (d, 1H); 7,56 (s, 1H); to 7.84 (DD, 1H); by 8.22 (DD, 1H).

NMR-FROM13(CDCl3+CD3D): 7,87; 36,11; 42,16; 45,33; 52,67; 54,52; 56,47; 61,97; 73,26; 101,17; 110,81; 115,49; 122,93; 128,63; 139,83; 144,28; 146,40; 149,27; 151,27; 151,64; 152,31; 153,82; 156,50; 157,71; 172,56.

IR (KBr): 1607; 1656; 1732; 2795; 3411.

Example 47: 5-ethyl-9,10-debtor-4,5-dihydro-5-hydroxy-12-piperidinomethyl-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., apply for 3,4-diferencia order to obtain ethyl-2-chloro-4-chloromethyl-6,7-debtor-3-chinainternational, which is treated by the method of example 30.d., using piperidine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as the Receive light green solid product so pl. 266-268oC.

NMR1H (DMSO): 0,86 (t, 3H); 1,42-1,49 (m, 6N); 1,85 (K, 2N); 2,47 (m, 4H); a 3.06 (d, 1H); 3,48 (d, 1H); 4,00 (K, 2N); 5,31 (s, 2H); 5,46 (DD, 2H); 6,04 (s, 1H); 7,37 (s, 1H); to 8.14 (m, 1H); 8,46 (m, 1H).

NMR-FROM13(DMSO): 8,43; 24,01; 25,8; 36,52; 42,56; 50,60; 54,29; 56,91; 61,41; 73,30; 99,81; 111,86; 115,67; 122,94; 130,10; 140,66; 144,49; 146,12; 153,18; 155,86; 159,14; 172,03.

IR (KBr): 1258; 1452; 1517; 1607; 1661; 1731; 2950; 3480.

Example 48: 5-ethyl-9,10-debtor-4,5-dihydro-5-hydroxy-12-dimethylaminomethyl-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., apply for 3,4-diferencia order to obtain ethyl-2-chloro-4-chloromethyl-6,7-debtor-3-chinainternational, which is treated by the method of example 30.d., using dimethylamine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j. example 11. The resulting product cyclist in accordance with method stage 11.k. Get a light beige solid product, so pl. 270oC.

NMR1H (DMSO): 0,86 (t, 3H); 1.85 to (K, 2N); 2,25 (C, 6N); is 3.08 (d, 1H); 3,47 (d, 1H); 3,95 (K, 2N); 5,28 (s, 2H); 5,46 (DD, 2H); the 6.06 (s, 1H); 7,37 (s, 1H); to 8.14 (s, 1H); 8,42 (s, 1H).

NMR-FROM13(D is IR (KBr): 1516; 1613; 1654; 1731; 3450.

Example 49: 9-chloro-5-ethyl-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

The method described in examples 30.A., 30.b. and 30.S., used for 3-chloro-4-methylaniline to obtain ethyl-2,7-dichloro-4-chloromethyl-6-methyl-3-chinainternational, which is treated by the method of example 30.d., using morpholine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11.

The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl. >300oC.

NMR1H (DMSO): of 0.87 (t, 3H); 1,84 (K, 2N); 2,50 (s, 4H); of 2.58 (s, 3H); of 3.07 (d, 1H); 3.46 in (d, 1H); of 3.57 (s, 4H); 4,08 (DD, 2H); and 5.30 (s, 2H); 5,51 (DD, 2H); the 6.06 (s, 1H); to 7.35 (s, 1H); 8,15 (s, 1H); to 8.41 (s, 1H).

NMR-FROM13(DMSO): 8,42; 20,57; 36,51; 42,55; 50,76; 53,46; 55,86; 61,42; 66,42; 73,29; 99,73; 122,78; 128,40; 130,10; 135,31; 136,26; 139,36; 144,61; 147,79; 152,81; 155,86; 159,16; 172,04.

IR (KBr): 1613; 1657; 1736; 3432.

Example 50: 9-chloro-5-ethyl-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

Way, opacimeter-3-chinainternational, which is treated according to the method of example 30.d., then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl. 262-268oC.

NMR1H (DMSO): of 0.87 (t, 3H); 1,86 (K, 2N); of 2.15 (s, 3H); 2,20-2,60 (m, 8H); 2,60 (s, 3H); 3,05 (d, 1H); 3,49 (d, 1H); 4.09 to (DD, 2H); 5,32 (s, 2H); 5,50 (DD, 2H); 6,05 (s, 1H); 7,37 (s, 1H); 8,21 (s, 1H); 8,43 (s, 1H).

NMR-FROM13(DMSO): 8,42; 20,56; 36,50; 42,55; 45,91; 50,81; 53,00; 54,94; 55,65; 61,43; 73,29; 79,36; 99,69; 122,75; 126,32; 128,37; 129,84; 135,25; 136,23; 139,87; 144,57; 147,75; 152,76; 155,87; 159,15; 172,04.

IR (KBr): 1607; 1658; 1733; 3424.

Example 51: 12-benzylmethylamine-9-chloro-5-ethyl-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

The method described in examples 30.A., 30.b. and 30.S., used for 3-chloro-4-methylaniline to obtain ethyl-2,7-dichloro-4-chloromethyl-6-methyl-3-chinainternational, which is treated by the method of example 30.d., using N-methylbenzylamine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan is the query result product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl. 272-278oC.

NMR1H (DMSO): 0,88 (t, 3H); of 1.85 (m, 2H); 2.13 and (s, 3H); to 2.55 (s, 3H); 3,10 (d, 1H); 3,50 (d, 1H); to 3.67 (s, 2H); of 4.05 (DD, 2H); and 5.30 (s, 2H); 5,39-to 5.57 (DD, 2H); 6,05 (c , 1H); of 7.36 (m, 6N); 8,15 (s, 1H); 8,31 (s, 1H).

NMR-FROM13(DMSO): 9,10; 21,15; 37,20; 42,86; 43,23; 51,32; 55,78; 62,10; 62,88; 73,99; 80,05; 100,44; 123,47; 126,99; 127,32; 128,09; 129,17; 129,96; 130,86; 135,75; 136,84; 139,51; 140,67; 145,38; 148,54; 153,50; 156,54; 159,85; 172,73.

IR (KBR): 1609; 1655; 1729; 3395.

Example 52: 12-(4-benzylpiperazine)-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

The method described in examples 30.A., 30.b. and 30.S., used for 3-chloro-4-methylaniline to obtain ethyl-2,7-dichloro-4-chloromethyl-6-methyl-3-chinainternational, which is treated by the method of example 30.d., using N-benzylpiperazine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11. The resulting product cyclist in accordance with method stage 11.k. Get a beige solid product, so pl. 244-249oC.

NMR1H (DMSO): 0,86 (t, 3H); to 1.83 (m, 2H); 2,38-2,60 (m, 8H); to 2.57 (s, 3H); is 3.08 (d, 1H); 3.46 in (c, 2H); 4,08 ( 53,54; 53,80; 56,35; 62,09; 62,84; 73,97; 97,67; 100,39; 123,45; 127,05; 127,75; 129,02; 129,63; 130,61; 135,95; 136,93; 139,14; 140,52; 145,27; 148,45; 153,47; 156,52; 159,83; 172,72.

IR (KBr): 1567; 1587; 1652; 1748; 3422.

Example 53: 9-chloro-5-ethyl-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

The method described in examples 30.A., 30.b. and 30.S., used for 3-chloro-4-methylaniline to obtain ethyl-2,7-dichloro-4-chloromethyl-6-methyl-3-chinainternational, which is treated by the method of example 30. d., using piperidine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl. 255oC (decomp.).

NMR1H (DMSO): 0,86 (t, 3H); 1,50 (m, 6N); of 1.84 (m, 2H); 2.50 each (m, 4H); of 2.58 (s, 3H); 3,05 (d, 1H); of 3.45 (d, 1H); Android 4.04 (m, 2H); 5,32 (s, 2H); 5,51 (DD, 2H); 6,10 (s, 1H); 7,37 (s, 1H); to 8.20 (s, 1H); 8,42 (s, 1H).

NMR-FROM13(DMSO): 9,11; 21,24; 24,70; 26,50; 37,20; 43,23; 51,43; 55,10; 57,21; 62,09; 73,99; 98,05; 100,38; 123,44; 127,10; 129,12; 130,59; 135,89; 136,91; 140,99; 145,31; 148,50; 153,52; 156,51; 159,85; 172,73.

IR (KBR): 1601; 1654; 1728; 3436.

Example 54: 12-(4-bentilee, described in examples 30.A., 30.b. and 30.S., used for 4-foronline order to obtain ethyl-2-chloro-4-chloromethyl-6-fluoro-3-chinainternational, which is treated by the method of example 30.d., using N-benzylpiperazine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j. example 11. The resulting product cyclist in accordance with method stage 11.k. Get white solid product, so pl. 262oC.

NMR1H (DMSO): of 0.87 (t, 3H); 1.85 to (K, 2N); is 2.37 (s, 4H); is 2.37 (s, 4H); of 3.07 (d, 1H); of 3.45 (s, 2H); 3,47 (d, 1H); 4,08 (K, 2N); 5,32 (s, 2H); 5,46 (DD, 2H); 6,03 (s, 1H); 7,35 (m, 5H); 7,38 (s, 1H); to 7.77 (m, 1H); to 8.20 (m, 2H).

NMR-FROM13(DMSO): 8,41; 36,49; 42,53; 50,65; 52,82; 53,03; 55,95; 61,41; 62,14; 72,3; 99,55; 109,31; 120,14; 120,40; 122,70; 127,05; 128,32; 128,55; 128,96; 130,40; 138,42; 139,65; 144,66; 145,83; 152,15; 155,89; 159,15; 161,57; 172,02.

IR (KBR): 740; 834; 1071; 1193; 1220; 1288; 1360; 1451; 1516; 1592; 1655; 1749; 2813; 2950; 3434.

Example 55: 12-(4-benzylpiperazine)-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

The method described in examples 30.A., 30.b. and 30.S., used for 3-fluoro-4-methylaniline to obtain ethyl-2-chloro-4-chloromethyl-7-fluoro-6-N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11. The resulting product cyclist in accordance with method stage 11.k. Get a light beige solid product, so pl. 259oC.

NMR1H (DMSO): 0,86 (t, 3H); 1.85 to (K, 2N); of 2.38 (m, 4H); 2.50 each (s, 4H); a 3.06 (d, 1H); to 3.36 (s, 3H); 3.46 in (s, 2H); 3,47 (d, 1H); 4,07 (K, 2H); from 5.29 (s, 2H); 5,46 (DD, 2H); of 6.02 (s, 1H); 7.23 percent-7,35 (m, 6N); of 7.8 (d, 1H); 8,35 (d, 1H).

NMR-FROM13(DMSO): 8,40; 15,45; 36,47; 42,54; 50,7; 52,84; 53,13; 55,81; 61,4; 62,14; 73,29; 99,57; 112,45; 122,61; 124,73; 127,05; 128,32; 128,96; 138,45; 139,81; 144,68; 152,63; 155,85; 159,15; 172,02.

IR (KBr): 1013; 1069; 1169; 1241; 1266; 1475; 1577; 1594; 1655; 1744.

Example 56: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-dimethylaminomethyl-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., used for 3-fluoro-4-methylaniline to obtain ethyl-2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-chinainternational, which is treated by the method of example 30.d., using dimethylamine instead of N-methylpiperazine, then restore in accordance with the method of example 30. that is, in the appropriate kinalimutan. The latter is subjected to interaction , with the way the stage 11. k. Get a light beige solid product, so pl. 184-190oC.

NMR1H (DMSO): 0,86 (t, 3H); 1.85 to (K, 2N); and 2.26 (s, 6N); 2,5 (s, 3H); 3,05 (d, 1H); 3,48 (d, 1H); 3,98 (K, 2N); 5,28 (s, 2H); 5,46 (DD, 2H); the 6.06 (s, 1H); 7,37 (s, 1H); to 7.84 (d, 1H); 8,35 (d, 1H).

NMR-FROM13(DMSO): 8,45; 15,50; 36,52; 45,59; 50,62; 57,36; 61,43; 73,33; 99,66; 112,29; 112,50; 122,67; 124,71; 126,99; 127,20; 127,44; 129,08; 140,16; 144,80; 148,82; 152,71; 155,89; 159,22; 160,75; 172,07.

IR (KBR): 1448; 1595; 1653; 1749; 2950; 3438.

Example 57: 5-ethyl-12-diethylaminomethyl-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

The method described in examples 30.A., 30.b. and 30.S., used for 3-fluoro-4-methylaniline to obtain ethyl-2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-chinainternational, which is treated by the method of example 30.d., using diethylamine instead of N-methylpiperazine, then restore in accordance with the method of example 30. that is, in the appropriate kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11. The resulting product cyclist in accordance with method stage 11. k. Get a light beige solid product, so pl. >270oC.

NMR1H (DMSO): of 0.87 (t, 3H); 1,04 (t, 6N); 1,86 (K, 2N); 2,50 (K, 2N); 2,54 (c, 3H); 2,56 (K, 2N); is 3.08 (d, 1H); 3,48 (d, 1H); 4,157; 36,5; 42,5; 46,68; 46,83; 46,99; 50,77; 51,85; 52,08; 61,44; 73,30; 99,60; 112,18; 112,36; 122,6; 124,6; 126,9; 127,1; 128,8; 141,45; 144,6; 148,6; 148,7; 152,65; 155,9; 159,1; 160,7; 163,2; 172,1.

IR (KBR): 1217; 1295; 1448; 1463; 1507; 1609; 1660; 1725; 2971; 3559.

The suspension of the above free base in absolute ethanol (50 ml/mmol) with subsequent treatment of ethanolic hydrogen chloride (2,5 N. , 5 EQ.) allows you to obtain the corresponding hydrochloride. Initially formed yellow solution, and then the precipitate, which is collected by filtration after concentration to 40% of the initial volume, and then washed with diethyl ether. Get a bright-yellow solid product, so pl. 269-272oC.

NMR1H (DMSO): of 0.87 (t, 3H); of 1.34 (m, 1H); 1,86 (K, 2N); of 2.56 (s, 3H); of 3.07 (d, 1H); 3,19 (m, 2H); 3,39 (m, 2H); 3,49 (d, 1H); equal to 4.97 (m, 2H); 5,41 (d, 1H); 5,54 (d, 1H); to 5.58 (s, 2H); between 6.08 (s, 1H); 7,42 (s, 1H); of 7.96 (d, 1H); 8,43 (d, 1H); 10,38 (s, 1H).

IR (KBr): 1039; 1070; 1226; 1282; 1509; 1654; 1724; 1744; 2921; 3409; 3489.

Example 58: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidino)-1H-oxepin[3', 4': 6,7] indolizino[1,2-b]quinoline-3,15(4H, 13H)-dione

The method described in examples 30.A., 30.b. and 30.S., used for 3-fluoro-4-methylaniline to obtain ethyl-2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-chinainternational, which is treated by the method of example 30. d., is.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl. >250oC.

NMR1H (DMSO): 1,00-0,80 (complex, 6N); 1,12 (K, 1H); 1,37 (s, 1H); 1.57 in (d, 3H); 1.85 to (K, 2N); a 2.13 (t, 2H); 2.82 from (s, 1H); 2,85 (s, 1H); 3,05 (d, 1H); of 3.25 (s, 3H); 3,48 (d, 1H); 4.04 the (K, 2N); 5,28 (c, 2H); of 5.39 (d, 1H); 5,52 (d, 1H); 6,03 (s, 1H); of 7.36 (s, 1H); of 7.82 (d, 1H); to 8.40 (d, 1H).

NMR-FROM13(DMSO): 0,29; 8,43; 13,68; 15,48; 19,40; 21,93; 23,23; 30,39; 34,20; 36,52; 42,55; 50,67; 53,84; 56,39; 57,67; 61,40; 73,32; 99,59; 112,49; 122,62; 124,80; 127,18; 129,10; 140,31; 144,58; 148,64; 152,69; 155,84; 159,19; 172,05.

IR (KBr): 1507; 1653; 1747; 3446.

Example 59: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-pyrrolidinyl-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., used for 3-fluoro-4-methylaniline to obtain ethyl-2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-chinainternational, which is treated by the method of example 30.d., using pyrrolidine instead of N-methylpiperazine, then restore in accordance with the method of example 30. that is, in the appropriate kinalimutan. The latter is subjected to interaction with connection (M), as described indicate the yellow solid product, so pl. >250oC.

NMR1H (DMSO): 0,86 (t, 3H); 1,72 (s, 4H); 1.85 to (K, 2N); to 2.57 (s, 4H); 3,05 (d, 1H); 3,28 (c, 3H); 3,48 (d, 1H); 4,18 (K, 2N); 5,28 (s, 2H); of 5.39 (d, 1H); 5,52 (d, 1H); 6,03 (s, 1H); of 7.36 (s, 1H); of 7.82 (d, 1H); 8,35 (d, 1H).

NMR-FROM13(DMSO): 0,37; 8,47; 15,57; 23,48; 36,53; 42,61; 50,61; 53,45; 54,09; 61,42; 73,33; 99,59; 112,37; 122,64; 124,51; 127,00; 127,25; 128,63; 140,65; 144,77; 148,65; 152,73; 155,87; 159,20; 162,00; 167,00; 172,07.

IR (KBr): 1608; 1656; 1729; 3400.

Example 60: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(1,2,5,6-tetrahydropyridine)-lH-oxepin[3', 4': 6,7] indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., used for 3-fluoro-4-methylaniline to obtain ethyl-2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-chinainternational, which is treated by the method of example 30.d., using 1,2,5,6-tetrahydropyridine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl. >250oC.

NMR1H (DMSO): 0,86 (t, 3H); 1.85 to (K, 2N); 2,08 (s, 2H); 3,03 (s, 2H); 3,05 (d, 1H); or 3.28 (s, 3H); 3,48 (d, 1H); 4,12 (d, 1H); 5,28 (s, 2H); 5,39 (d; 50,68; 52,52; 55,81; 61,42; 73,33; 99,62; 112,53; 122,66; 124,78; 125,03; 127,09; 127,19; 131,73; 139,98; 144,76; 148,79; 152,73; 155,86; 159,19; 160,76; 163,25; 172,07.

IR (KBr): 1605; 1656; 1733; 3451.

Example 61: 12-diisobutylamine-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

The method described in examples 30.A., 30.b. and 30.S., used for 3-fluoro-4-methylaniline to obtain ethyl-2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-chinainternational, which is treated by the method of example 30.d., using diisobutylamine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl. >250oC.

NMR1H (DMSO): 0.75 in (d, N); of 0.87 (t, 3H); to 1.83 (m, 4H); 2,15 (d, 1H); 2,48 (s, 3H); to 3.06 (d, 1H); 3,47 (d, 1H); 4,01 (K, 2N); 5,28 (s, 2H); of 5.39 (d, 1H); of 5.53 (d, 1H); 6,03 (s, 1H); 7,37 (s, 1H); 7,83 (d, 1H); 8,49 (d, 1H).

NMR-FROM13(DMSO): 9,09; 16,14; 21,73; 26,57; 26,70; 37,15; 43,14; 51,05; 55,49; 62,08; 64,74; 73,98; 100,42; 113,03; 123,38; 125,58; 127,12; 127,32; 128,59; 130,27; 141,32; 145,51; 149,38; 149,51; 153,20; 156,62; 159,86; 161,31; 163,79; 172,72.

IR (KBr): 1599; 1656; 1747; 2796; 3448.

-b]quinoline-3,15(4H, 13H)-dione

The method described in examples 30.A., 30.b. and 30.S., used for 3-fluoro-4-methoxyaniline order to obtain ethyl-2-chloro-4-chloromethyl-7-fluoro-6-methoxy-3-chinainternational, which is treated by the method of example 30.A. then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j.example 11. The resulting product cyclist in accordance with method stage 11.k. Get a light-yellow solid product, so pl. 274oC.

NMR1H (DMSO): 0,86 (t, 3H); 1.85 to (K, 2N); of 2.15 (s, 3H); 2,31 (m, 4H); 2,47 (m, 4H); a 3.06 (d, 1H); 3,47 (d, 1H); of 4.05 (m, 2H); of 4.05 (s, 3H); 5,28 (s, 2H); of 5.45 (DD, 2H); 6,05 (s, 1H); to 7.35 (s, 1H); 7,87 (d, 1H); 7,94 (d, 1H).

NMR-FROM13(DMSO): 8,44; 36,53; 45,58; 45,95; 50,68; 52,86; 55,07; 56,20; 56,47; 61,45; 73,32; 99,19; 105,90; 113,74; 113,91; 122,22; 125,60; 129,46; 138,83; 144,51; 144,62; 144,94; 147,85; 147,98; 150,96; 152,82; 155,34; 155,96; 159,19; 172,09.

IR (KBr): 1270; 1515; 1594; 1648; 1747; 2950; 3438.

Example 63: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., used for 3-fluoro-4-methoxyaniline order to obtain ethyl-2-chloro-4-chloromethyl-7-fluoro-6-methoxy-3-chinainternational liveout in accordance with the method of example 30. that is, in the appropriate kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11. The resulting product cyclist in accordance with method stage 11. k. Get a light-green solid product, so pl. >275oC.

NMR1H (DMSO): 0,86 (t, 3H); 1,42 of 1.50 (m, 6N); 1,84 (K, 2N); of 2.50 (m, 4H); 3,05 (d, 1H); 3,48 (d, 1H); is 4.03 (s, 2H); of 4.05 (s, 3H); and 5.30 (s, 2H); of 5.45 (DD, 2H); of 6.02 (s, 1H); 7,35 (c, 1H); 7.9 in (d, 1H); to 7.99 (d, 1H).

NMR-FROM13(DMSO): 8,44; 24,07; 25,9; 36,54; 42,57; 50,60; 54,26; 56,40; 57,11; 61,42; 73,33; 99,17; 105,97; 113,75; 113,92; 122,21; 125,66; 129,46; 139,23; 144,54; 144,98; 147,94; 151,0; 152,82; 155,34; 155,89; 159,20; 172,07.

IR (KBr): 860; 1057; 1270; 1514; 1656; 1748; 2857; 2932; 3397.

The suspension of the above free base in absolute ethanol (50 ml/mmol) with subsequent treatment of ethanolic hydrogen chloride (2,5 N. , 5 EQ.) allows you to obtain the corresponding hydrochloride. Initially formed yellow solution, and then the precipitate, which is collected by filtration after concentration to 40% of the initial volume, and then washed with ether. Get a pale yellow solid product, so pl. 264oC.

NMR1H (DMSO): 0,86 (t, 3H); to 1.42 (m, 1H); 1.70 to of 1.85 (m, 7H); a 3.06 (d, 1H); to 3.33 (m, 4H); 3,47 (m, 1H); 4,19 (s, 3H); 5,00 (s, 2H); of 5.40 (d, 1H); 5,54 (d, 1H); 5,61 (s, 2H); of 6.02 (s, 1H);78; 73,97; 100,06; 106,96; 107,14; 114,80; 123,20; 126,58; 130,48; 134,14; 145,33; 145,48; 149,49; 149,62; 151,76; 153,84; 156,36; 156,69; 159,76; 172,73.

IR (KBr): 1010; 1072; 1240; 1271; 1469; 1511; 1574; 1598; 1648; 1734; 2525; 2944; 3430; 3507.

Example 64: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-dimethylaminomethyl-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., used for 3-chloro-4-methoxyaniline to obtain ethyl-2,7-dichloro-4-chloromethyl-6-methoxy-3-chinainternational, which is treated by the method of example 30.d., using dimethylamine instead of N-methylpiperazine, then restore in accordance with the method of example 30. that is, in the appropriate kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl. >250oC.

NMR1H (DMSO): 0,86 (t, 3H); 1,84 (K, 2N); to 2.29 (s, 6N); a 3.06 (d, 1H); 3.42 points (d, 1H); 3,98 (K, 2N); of 4.05 (s, 3H); at 5.27 (s, 2H); of 5.45 (s, 2H); 5,95 (s, 1H); to 7.32 (s, 1H); 7,82 (c, 1H); 8,19 (s, 1H).

NMR-FROM13(DMSO): 8,41; 36,50; 42,55; 45,58; 50,62; 56,70; 57,42; 61,42; 73,29; 99,28; 104,66; 122,34; 126,92; 127,55; 129,89; 130,04; 139,19; 144,20; 144,81; 151,08; 153,15; 155,91; 159,18; 172,04.

IR (KBr): 1048; 1242; 1482; 1611; 1659; 1730; 3301; 3417.

Example 65: Guide the in-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., used for 3-chloro-4-methoxyaniline to obtain ethyl-2,7-dichloro-4-chloromethyl-6-methoxy-3-chinainternational, which is treated by the method of example 30.d., using piperidine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11. The resulting product cyclist in accordance with method stage 11.k. Thus obtained free base is suspended in absolute ethanol (50 ml/mmol), then treated with ethanolic hydrogen chloride (2,5 N. , 5 EQ. ). Initially formed yellow solution, and then the precipitate, which is collected by filtration after concentration to 40% of the initial volume, and then washed with ether. Get orange solid product, so pl. >250oC.

NMR1H (DMSO): 0,86 (t, 3H); 1,43 (K, 1H); 1,70 (d, 1H); to 1.76 (m, 2H); to 1.86 (m, 4H); of 3.07 (d, 1H); or 3.28 (m, 1H); 3,47 (m, 3H); 4,20 (s, 3H); 5,00 (K, 2N); 5,41 (d, 1H); 5,54 (d, 1H); 5,62 (s, 1H); 6,10 (s, 1H); of 7.36 (s, 1H); 7,88 (s, 1H); 8,31 (s, 1H).

NMR-FROM13(CF3D): 8,44; 22,11; 24,79; 38,27; 43,51; 54,28; 56,01; 58,51; 58,75; 64,23; 77,59; 104,22; 110,49; 124,68; 129,44; 131,91; 136,61; 140,01; 141,33; 144,72; 158,25;ro-5-hydroxy-10-methoxy-12-(1,2,5,6-tetrahydropyridine)-lH-oxepin[3', 4': 6,7] indolizino[1,2-b] quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., used for 4-methoxyaniline order to obtain ethyl-2-chloro-4-chloromethyl-6-methoxy-3-chinainternational, which is treated by the method of example 30.d., using 1,2,5,6-tetrahydropyridine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11. The resulting product cyclist in accordance with method stage 11.k. Thus obtained free base is suspended in absolute ethanol (50 ml/mmol), then treated with ethanolic hydrogen chloride (2,5 N. , 5 EQ. ). Initially formed yellow solution, and then the precipitate, which is collected by filtration after concentration to 40% of the initial volume, and then washed with ether. Receives a yellow solid product, so pl. >250oC.

NMR1H (DMSO): 0,86 (t, 3H); 1,87 (K, 2N); 2,32 (m, 1H); of 3.07 (d, 1H); 3,48 (m, 3H); to 3.89 (m, 8H); 4,06 (s, 3H); to 5.08 (m, 2H); of 5.40 (d, 1H); 5,54 (d, 1H); 5,63 (K, 2N); 5,67(d, 2H); to 5.93 (d, 2H); 7,37 (s, 1H); to 7.59 (K, 1H); 7,79 (d, 1H); to 8.14 (d, 1H); 1080 (s, 1H).

NMR-FROM13(DMSO): 8,47; 25,97; 36,40; 42,55; 49,75; 50,25; 50,61; 52,36; 56,05; 61,41653; 1746; 2363; 3373.

Example 67: 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperidino)-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., used for 4-methoxyaniline order to obtain ethyl-2-chloro-4-chloromethyl-6-methoxy-3-chinainternational, which is treated by the method of example 30.d., using 4-methylpiperidin instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl. >250oC.

NMR1H (CF3OD): 1,17 (m, 6N); of 1.62 (m, 2H); 1,89 (s, 1H); 2,07 (K, 2N); to 2.25 (m, 2H); of 3.54 (m, 3H); to 3.89 (d, 1H); was 4.02 (s, 2H); 4,19 (s, 3H); 7,94 (s, 1H); 8,10 (m, 1H); 8,29 (s, 1H); and 8.50 (m, 1H).

NMR-FROM13(CF3COOD): 8,43; 13,79; 17,43; 20,89; 30,89; 30,01; 32,85; 38,26; 43,50; 54,13; 56,09; 57,87; 58,27; 64,22; 77,57; 107,37; 110,56; 125,75; 129,36; 129,42; 132,78; 136,04; 136,65; 139,91; 140,38; 144,31; 158,30; 161,94; 164,90; 178,84.

IR (KBr): 825; 1056; 1230; 1260; 1516; 1641; 1655; 1736; 2921; 3395.

Example 68: 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperazine)-1H-oxepin[3',4':6,7]indolizino[1,2-b]China is of ethyl-2-chloro-4-chloromethyl-6-methoxy-3-chinainternational, which is treated according to the method of example 30. d., then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl. 215-219oC.

NMR1H (DMSO): of 0.85 (t, 3H); of 1.85 (m, 2H); of 2.15 (s, 3H); to 2.35 (m, 4H); 2,5 (m, 4H); of 3.25 (DD, 2H); of 3.95 (s, 3H); of 4.05 (s, 2H); 5,3 (s, 2H); of 5.45 (DD, 2H); 6 (s,1H); and 7.3 (s,1H); 7.5 (d, 1H), and 7.7 (s, 1H); with 8.05 (d, 1H).

NMR-FROM13(DMSO): 9,12; 14,36; 20,08; 23,93; 46,61; 51,35; 53,58; 55,71; 56,34; 56,73; 58,37; 62,11; 74,03; 99,62; 104,49; 122,66; 123,11; 129,54; 130,53; 131,82; 139,05; 145,3; 145,86; 150,67; 156,62; 158,71; 159,91; 172,77.

IR (KBr): 1590; 1624; 1655; 1744; 2801; 2935; 3423.

Example 69: 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-pyrrolidinyl-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

The method described in examples 30.A., 30.b. and 30.S., used for 4-methoxyaniline order to obtain ethyl-2-chloro-4-chloromethyl-6-methoxy-3-chinainternational, which is treated by the method of example 30.d., using pyrrolidine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The last subject is isout in accordance with method stage 11.k. Receives a yellow solid product, so pl. >250oC.

NMR1H (DMSO): of 0.85 (t, 3H); 1,7 (s, 4H); 1.85 to (K, 2N); to 2.55 (s, 4H); of 3.25 (DD, 2H); from 3.9 (s, 3H); 4,15 (s, 2H); 5.25 in (s, 2H); of 5.45 (DD, 2H); 6 (c, 1H); to 7.35 (s, 1H); 7.5 (d, 1H), and 7.7 (s, 1H); with 8.05 (d, 1H).

NMR-FROM13(DMSO): 9,68; 24,74; 51,8; 54,71; 55,25; 56,3; 56,87; 62,3; 62,64; 74,5; 100,14; 104,8; 104,92; 123,19; 123,45; 129,79; 130,49; 132,32; 132,50; 140,5; 145,83; 146,4; 151,27; 157,15; 159,25; 160,45; 173,3.

IR (KBr): 1255; 1516; 1535; 1613; 1655; 1735; 3438; 3762; 3830.

Example 70: 12-(4-benzylpiperazine)-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

The method described in examples 30.A., 30.b. and 30.S., used for 4-methoxyaniline order to obtain ethyl-2-chloro-4-chloromethyl-6-methoxy-3-chinainternational, which is treated by the method of example 30.A., using N-benzylpiperazine instead of N-methylpiperazine, then restore in accordance with the method of example 30.E. in the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11.j. example 11. The resulting product cyclist in accordance with method stage 11.k. Get a beige solid product, so pl. >250oC.

NMR1H (DMSO): of 0.85 (t, 3H); 1.85 to (K, 2N) and 2.4 (m, 4H); to 2.55 (m, 4H); of 3.25 (DD, 2H); 3.45 points (c, 2H); 3.95 to (c, 3H); of 4.05 (s, 2H)54,98; 55,1; 60,1; 60,35; 61,11; 72,26; 97,86; 102,6; 102,76; 120,9; 121; 121,2; 121,4; 126; 127,25; 127,77; 127,88; 128,76; 130,13; 130,2; 137,25; 137,36; 143,53; 144,08; 148,86; 156,86; 156,95; 158,15; 171,02.

IR (KBr): 1235; 1259; 1517; 1586; 1614; 1654; 1747; 2927; 3450; 3762; 3848.

The suspension of the above free base in absolute ethanol (50 ml/mmol) with subsequent treatment of ethanolic hydrogen chloride (2,5 N. , 5 EQ.) allows you to obtain the corresponding hydrochloride. Initially formed yellow solution, and then the precipitate, which is collected by filtration after concentration to 40% of the initial volume, and then washed with ether. Receives a yellow solid product, so pl.> 250oC.

NMR1H (DMSO): of 0.85 (t, 3H); 1.85 to (K, 2N); 2,5 (s, 2H); to 2.65 (m,2H); 3 (m, 2H); 3,2 (m, 2H); at 3.35 (DD, 2H); at 3.35 (s, 2H); of 3.95 (s, 3H); 4,15 (s, 2H); 4,3 (s, 2H); 5,3 (s, 2H); of 5.45 (DD, 2H); and 7.3 (s, 1H); 7,4 (s, 2H); at 7.55 (m, 2H), and 7.7 (s, 1H); with 8.05 (d, 1H); 10,45 (s, 1H).

IR (KBR): 1207; 1233; 1439; 1449; 1458; 1508; 1610; 1620; 1655; 1727; 3398.

Example 71: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidino)-1H-oxepin[3', 4': 6,7] indolizino [1,2-b] quinoline-3,15(4H, 13H)-dione

The method described in examples 30.A., 30.b. and 30.S., used for 3-chloro-4-methylaniline to obtain ethyl-2,7-dichloro-4-chloromethyl-6-methyl-3-chinainternational, which is treated by the method of example 30.d., the corresponding kinalimutan. The latter is subjected to interaction with the compound (M) as described in stage 11. j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl. >275oC.

NMR1H (DMSO): 0,86 (m, 6N); to 1.15 (m, 2H); to 1.37 (m, 1H) and 1.60 (m, 2H); of 1.80 (m, 2H); 2,10 (m, 2H); 2,60 (s, 3H); 2,80 (m, 2H); 3,05 (d, 1H); 3,48 (d, 1H); was 4.02 (s, 2H); and 5.30 (s, 2H); of 5.45 (DD, 2H); of 6.02 (s, 1H); 7,40 (c, 1H); to 8.20 (s, 1H); to 8.40 (s, 1H).

NMR-FROM13(DMSO): 9,10; 21,28; 22,61; 31,07; 34,89; 37,18; 43,22; 54,53; 56,83; 62,10; 73,94; 80,06; 100,43; 123,41; 127,08; 129,11; 130,58; 135,88; 136,89; 141,00; 145,28; 148,49; 153,51; 156,60; 159,85; 172,77; 174,05.

IR (KBr); 1605; 1657; 1734; 3342.

Example 72: 10-benzyloxy-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

The method described in stage 11.i. used for 3-fluoro-4-methoxyacetanilide order application process 2-chloro-7-fluoro-6-methoxy-quinoline-3-carbaldehyde, which is treated with excess tribromide boron at ambient temperature for 24 hours. Get 2-chloro-7-fluoro-6-hydroxyquinolin-3-carbaldehyde, which O-benzilic in dimethylformamide in the presence of benzylbromide and potassium carbonate to obtain 6-benzyloxy-2-chloro-7-ftorhinolon-3-carbaldehyde, which is reactivated by sodium borohydride in peteano in stage 11.j. example 11. The resulting product cyclist in accordance with method stage 11.k. Receives a yellow solid product, so pl. >275oC.

NMR1H (DMSO): 0,86 (t, 3H); 1.85 to (K, 2N); 3,05 (d, 1H); 5.25 in (s, 2H); lower than the 5.37 (s, 2H); of 5.45 (DD, 2H); 6,05 (s, 1H); 7,4-7,6 (m, 5H); 7,88 (d, 1H); to 7.95 (d, 1H); 8,56 (s, 1H).

Example 73: 5-ethyl-9-fluoro-4,5-dihydro-5,10-dihydroxy-1H-oxepin[3',4': 6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

The compound of example 72 is subjected to hydrogenolysis in accordance with example 14. Receives a yellow solid product, so pl. >275oC.

NMR1H (DMSO): 0,86 (t, 3H); 1.85 to (K, 2N); 3,05 (d, 1H); 5.25 in (s, 2H); lower than the 5.37 (s, 2H); of 5.45 (DD, 2H); 6,05 (s, 1H); 7,8 (d, 1H); of 7.90 (d, 1H); 8,56 (s, 1H).

Pharmacological study of the products according to the invention

1. The study of relaxation activity of DNA induced by topoisomerase 1.

All reactions were performed in 20 μl reaction buffer consisting of 50 mm Tris-Hcl (pH 7.5), 50 mm KCl, 0.5 mm dithiothreitol, 10 mm MgCl2, 0.1 mm ethyldimethylammonium acid (edtc), 30 μg/ml bovine serum albumin and 300 ng of supercoiled pUC19 (Pharmacia Biotech, Orsay, France) in the presence or in the absence of the investigated compounds at certain concentrations. All compound initial is stillyoung water. The final concentration of DMSO should not exceed 1% (vol./vol.). The reaction was initiated by adding units of DNA topoisomerase 1 purified from calf thymus (Gibco-BRL, Paisley, United Kingdom) and held for 15 minutes at 37oC. the Reaction was stopped by adding 3 μl of a mixture containing 1% sodium dodecyl sulfate with a concentration of 1%, 20 mm etc and 500 μg/ml proteinase K (Boehringer Mannheim, Meilan, France). After an additional incubation period of 30 minutes at 37oWith added 2 μl of carrier buffer containing 10 mm Na2HPO4, 0.3% Bromphenol blue and 16% of ficoll in the samples that were subjected to electrophoresis on agarose gel at 1.2% At 1 V/cm for 20 hours in a buffer containing 36 mm Tris-Hcl at pH of 7.8, 30 mm Na2HPO4, 1 mm etc and 2 μg/ml of chloroquine. The gels showed 2 µg/ml ethidium bromide, photographed under ultraviolet light at 312 nm with the camera and the fluorescence intensity was measured with the use of video analyzers bioProfil (Vilber Lourmat, Lyon, France) to determine the percentage of relaksirano DNA. Each experiment was performed at least three times in duplicate.

In each experiment, the supercoiled plasmid DNA is incubated in itself of Italia supercoiled plasmid DNA is incubated in the presence of 500 μm of the investigated compounds in the presence of an enzyme or no enzyme plus the studied compound at concentrations of 10 μm, 100 μm, 200 μm and 500 μm. As indicated in the table.1, the compounds of examples 2, 3, 4, 9, 10 and 11 inhibit in a dose-dependent manner relaxation activity induced by topoisomerase 1.

2. The study of cell proliferation

A. This study used eight tumor cell lines: L1210 (murine leukemia lymphocytes), NST and LOVO (cell lines adenocarcinoma of human colon), A (carcinoma of the lung in humans), A, U373 and U87 (human glioblastoma). All these lines were obtained from American type culture collection (ATSS), Rockville, Md. Suspension cell cultures of L1210 were cultured in modified according to the method of Dulbecco environment Needle (DMEM) (BioWhitaker, Verviers, Belgium) with 10% fetal calf serum inactivated by heating, 2 mm glutamine, 50 M Ie/ml penicillin and 50 µg/ml streptomycin. Cells NT multivariable in monolayer cultures in medium McCoy's 5A (Gibco, Paisley, UK) with 10% fetal calf serum inactivated by heating, 2 mm glutamine and 50 μg/ml gentamicin. Other cells were cultured in modified according to the method of Earl essential nutrient medium (EMEM; Gibco, Paisley, UK) with 5% fetal pH is omicini. All cell lines were cultured at 37oWith in a humid atmosphere containing 95% air and 5% CO2.

The inhibition of proliferation of tumor cell lines was determined using MTT test. 1500 L1210 cells in culture medium (in accordance with the requirements of the environment for cells) were cultivated in well microwell plate (for tissue cultures: 96 wells, horizontal basis) for 24 hours before processing the test compounds. For these studies the dose - response cells were incubated with each test compound or the corresponding solvent (control) for 48 hours in the final concentration range from 110-10110-4M. All compounds were dissolved before use in dimethyl sulfoxide (DMSO) at a concentration of 50 mm. Other cultivation of drugs was carried out by the cultural environment. The final concentration of DMSO in none of the cases did not exceed 0.2% (vol./vol.). As a control drug solutions were replaced with the solvent, which is serially diluted in the same way that compound.

After an incubation period, each well was added marking MTT reagent (bromide 3-[4,5-dimethylthiazole for 4 hours at 37oC in humidified atmosphere. This stage allows the mitochondrial dehydrogenases of living cells to turn yellow salt tetrazole MTT to purple-red crystals of formazan. The supernatant is removed and the formed crystals formazan dissolved in DMSO. The obtained colored solution was evaluated quantitatively by measuring the absorption at 570 nm using multicoverage scanning spectrophotometer. Data on cell proliferation is expressed as the percentage of living cells in treated wells divided by the number of living cells in the control. Each point represents the average of three independent experiments, each experiment is six definitions.

For each of the other cell lines (NST, LOVO, A, A, U373, U87) from 1000 to 2000 cells were inoculated in a well microwell plate for 24 hours before treatment drugs. They were incubated with each of the tested compounds or the corresponding solvent (control) for 72 hours for a final concentration in the range from 110-10110-6M.

The results are expressed in percent calculated proliferation as optical density (OD) of cells treated with the drug were preparatively cell proliferation in a dose-dependent manner.

b. This study used nine tumor cell lines: RS, DU145 (cell line prostate cancer man), MCF7 and MCF7-ADR (cell lines of the breast, the symbol "ADR" is used to indicate that the line is resistant to adriamycin), A (human lung adenocarcinoma), NT (cell line adenocarcinoma of human colon), 24s, Tg (cell line aperture person, T24r's ustoichivy to adriamycin among others). Line RS, DU145 and A were obtained from the American type culture collection (ATS, Rockville, Md). Cells MCF7 and MCF7-ADR were kindly provided by Dr.Jacques Soudon (Pharmacell, Paris, France). Cells T24s and Tg were provided by Others.Robert Kiss (Free University, Brussels, Belgium). Cells NT cultured in a single layer cultures 4.5 g/l medium DMEM (Gibco, Paisley, United Kingdom), supplemented with 10% V / V heat inactivated fetal calf serum + 2 mm glutamine and 50 μg/ml gentamicin (Gibco, Paisley, United Kingdom). Other cells were cultured in modified according to the method of Earl essential medium DMEM with 4.5 g/l (Gibco, Paisley, United Kingdom), supplemented with 10% V / V heat inactivated fetal calf serum, 2 mm glutamine (Gibco, Paisley, United Queens of the ri 37oWith in a humid atmosphere containing 95% air and 5% CO2.

The inhibition of proliferation of tumor cell lines was determined using a colorimetric test WST1. From 500 to 4000 cells in culture medium (in accordance with the requirements of the cellular environment) were sown in well microwell plate (96 wells, horizontal basis) for 24 hours before processing the test compounds. For these studies the concentration-response cells were incubated with each of the tested compounds or the corresponding solvent (control) for 72 hours for a final concentration in the range from 1x10-13to 1x10-5M. All compounds were dissolved in dimethyl sulfoxide (DMSO) or water for water soluble compounds. Subsequent dilution of the compounds of the present invention were carried out in culture medium so that the final concentration of DMSO when it is part of the medium composition was always 0.1% (vol./vol.). As the control solutions of the compounds were replaced by the solvent, which was serially diluted in the same way that compound.

After incubation each well add marking agent WST1 (4-[3-(4-itfinal) up to 4 hours at 37oWith in a humid atmosphere. This stage allows the mitochondrial dehydrogenases of living cells to turn orange salt tetrazole WST1 in the purple-red crystals of formazan. The obtained colored solutions assess quantitatively, taking readings for the two beams (450 and 690 nm) using multicoverage scanning spectrophotometer.

The results are expressed as the concentration table, expressed in mol/l, containing 50% inhibiting concentration (IC50). They are presented in the table. 3A and 3B. Examples in which the number shall be followed by the letter "C" correspond to the salts of the compounds. Cpt, Adr and Tpt are abbreviations of camptothecin, adriamycin and topotecan, respectively.

1. The compound of formula (I) or formula (II)

< / BR>
< / BR>
in racemic or enantiomeric form or as a combination of these forms, where R1represents lower alkyl; R2, R3and R4represent, independently, H, halogen, lower alkyl, (CH2)mNR6R7, (CH2)mOR6, (CH2)mC(O)R8, (CH2)n[N= X] , substituted or unsubstituted aryl or lower arylalkyl where the Deputy is a lower hydroxyalkyl, and CH2and O; R5represents H, lower alkyl, (CH2)mNR6R7or (CH2)n[N= X] , substituted or unsubstituted aryl or lower arylalkyl radical, where the Deputy is a lower alkyl; R6and R7represent, independently, H, lower alkyl, cycloalkyl or lower arylalkyl; R8represents the lowest hydroxyalkyl; R9represents H, lower alkyl or benzyl; R16represents H or or21; R17is a OR6; R18and R19represent, independently, H, halogen or lower alkyl; R20represents H; R21represents H, lower alkyl, or Cho; m is an integer from 0 to 6; n is 1 or 2; and [N=X] is a 4-7-membered heterocyclic group, X represents a chain necessary to complete the specified heterocyclic group and selected from the group comprising O, CH2, SN, N, and NR9; or its pharmaceutically acceptable salt.

2. Connection on p. 1, wherein R2represents a hydrogen or halogen atom; R3represents a halogen atom, lower alkyl or lower alkoxy; R4the submitted the t a hydrogen atom; or its pharmaceutically acceptable salt.

3. Connection on p. 2, wherein R5is aminoalkyl, or its pharmaceutically acceptable salt.

4. Connection on p. 1, wherein the compound is selected from the group including

hydrochloride 5-ethyl-9,10-debtor-4,5-dihydro-5-hydroxy-12-(1,2,5,6-tetrahydropyridine)-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-12-(4-methylpiperidino)-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-12-pyrrolidinyl-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-12-(4-methylpiperazine)-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-12-piperidinomethyl-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-12-dimethylaminomethyl-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-12-morpholinomethyl-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-12-(4-methylpiperazine)-1H-oaks is-10-methyl-12-morpholinomethyl-1H-oxepin[3', 4': 6,7] indolizino[1,2-b] quinoline-3,15(4H,13H)-dione

12-(4-benzylpiperazine)-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

9-chloro-5-ethyl-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

12-(4-benzylpiperazine)-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

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

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

12-diisobutylamine-5-ethyl-9-fluoro-4,5-dihydr and-10-methoxy-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-methoxy-12-piperidinomethyl-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-dimethylaminomethyl-1H-oxepin[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

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

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

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

10-benzyloxy-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-1H-oxepin[3', 4': 6,7]indolenine-3,15(4H,13H)-dione;

or its pharmaceutically acceptable salt.

5. Connection on p. 4, characterized in that the said compound is selected from the following compounds:

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

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

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

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

or its pharmaceutically acceptable salt.

6. The compound according to any one of paragraphs.1-5 or its pharmaceutically acceptable salt having the ability to inhibit toposa the action, containing as active ingredient at least one of the compounds according to any one of paragraphs.1-5 or their pharmaceutically acceptable salts.

 

Same patents:

The invention relates to a new class of chemical compounds, namely to derive a new heterocyclic system - tetrabenazine[3,4-b:3',4'-f: 3", 4"-j: 3"', 4"'-n-[1,4,5,8,9,12,13,16]-actuatable[14.2.2]eicosa-4,8,12-triens General formula (I), where R1- R4= H, lower alkyl or lower alkyl containing functional groups, such as or SIG5, SR5, NR5R6, СОNR5R6or СООR7where R5, R6, R7= H, lower alkyl, or R2+ R3and/or R1+ R4together with the neighboring carbon atoms pieperazinove cycle form an alicyclic, benzene or heterocyclic annelirovannymi cycle

The invention relates to water-soluble derivative of camptothecin described by formula (I)

< / BR>
where n = 1 or 2; 1) R1and R2taken separately, represent hydrogen, lower alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, lower alkoxy lower alkyl; 2) R1represents hydrogen, lower alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl or lower alkoxy lower alkyl; R2is-COR3where R3represents hydrogen, lower alkyl, pergola-lower alkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl, lower alkyl, lower alkenyl, hydroxy lower alkyl, lower alkoxy, lower alkoxy lower alkyl; 3) R1and R2taken together with the connecting nitrogen atom form a saturated 3-7-atom heterocyclic group of formula 1A

< / BR>
where Y represents O, S, CH2, NR4where R4represents hydrogen, lower alkyl, pergola-lower alkyl, aryl, aryl substituted by one or more substituents selected from the group comprising lower alkyloxy lower alkyl, or COR5where R5represents hydrogen, lower alkyl, pergola-lower alkyl, lower alkoxy, aryl, aryl substituted by one or more substituents selected from the group comprising lower alkyl, pergola-lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl; and their pharmaceutically acceptable salts, their use for the treatment of tumors and methods of preparation

The invention relates to novel analogues of camptothecin formula (1), where R1- alkyl, alkylen, quinil, R2, R3, R4- H, halogen, halogenated, alkyl, alkenyl, -(CH2)mOR6, unsubstituted or substituted phenyl or phenylalkyl or R3and R4form together a chain with 3 or 4 members in which there may be elements of CH, CH2, O, N, or NR9, R3-H, halogen, halogenated, alkyl, alkoxy, substituted or unsubstituted phenyl or phenylalkyl, R6-H, alkyl, R9-H, alkyl, R18and R19-H, halogen, alkyl, alkoxy, hydroxy, R20-H, halogen, Rp-H, -C(O)-A-NR22R23where A - alkalinity radical, R22and R23- H, alkyl, m = 0 to 6 if Rp-H, R3and R4together form a chain with 3 or 4 members

The invention relates to a group of new compounds katoteshikufu General formula I, where R1- fully stereometric nonpolar side chain of amino acids, presents alkyl radical which has up to 4 carbon atoms; R2- basic side chain amino acids, which the radical of the formula -(CH2)n-R3and R3= NH2,

< / BR>
and n is 1-4, and their salts, stereoisomers and mixtures of stereoisomers; two methods of producing these compounds, and to a medicinal product which is able to inhibit the growth of tumors or slow their growth

The invention relates to the derivatives of camptothecin, method of their production, to their use as active ingredients for the preparation of drugs suitable for treatment of tumors, and to pharmaceutical preparations containing them

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)

The invention relates to new derivatives of camptothecin with enhanced antitumor activity, and intermediate products for their production

The invention relates to the field of medicine

The invention relates to new alkaloids of the formula I

< / BR>
present in various parts of Mappia foetida, and their pharmaceutical use and use them as the new synthons for preparing compounds with antitumor and antiviral activity, the same products are new synthons for new analogues of camptothecin and palidino

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The invention relates to bellrowan-carbolines, formula I, where R3denotes-CO-R1or group (a); R1- C1-C6alkoxy; R2- N2C1-C4alkyl, C1-C4alkoxy - C1-C2alkyl; And -- 5-6-membered unsaturated cycle, in which 1-2 carbon atoms may be replaced by N, O and/or S, which may be substituted with one R5or R6; R5and R6identical or different, denote H, C1-C6alkyl, NR7R8C1-C6alkyl which may be substituted by hydroxyl or C1-C4alkoxyl, phenyl, 5-6-membered heteroaryl residue, which contains one or two atoms of N, O or S, and phenyl and heteroaryl residue may be substituted C1-C4the alkyl, C1-C4alkoxyl, halogen, or R5and R6together,- CH2)nwhere n = 4; R7and R8- H, C1-C4alkyl, acyl, as well as their isomers, tautomers and salts

The invention relates to tricyclic 5,6-dihydro-N-pyrazolo [3,4-c] -1,2,4-triazolo[4,3-a]pyridinium, which have a selective inhibitory activity against phosphodiesterase (PDE) type IV or tumor-specific factor necrosis (TNF) and therefore effective in the treatment of asthma, arthritis, bronchitis, chronic obstructive Airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, such as AIDS, sepsis, septic shock and other diseases, in particular cachexia, causing the formation of tumor-specific factor necrosis
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