New tetracyclic analogues of camptothecin, methods for their preparation, intermediate compounds and pharmaceutical composition based on them

 

The invention relates to tetracyclic analogues of camptothecins formula (I), where R1, R2, R3, R4, R5and R10such as defined in the claims. Also described intermediate compounds and pharmaceutical composition for inhibiting topoisomerase I and II. The invention can be used in medicine as a therapeutic agent for the treatment of cancer. The technical result obtained new compounds possess valuable pharmacological properties. 12 C. and 4 h.p. f-crystals, 2 PL.

Description text in facsimile form (see graphic part).

Claims

1. The compound of General formula (I)

in which R1denotes lower alkyl;

R2, R3, R4represent, independently, a hydrogen atom, a lower alkoxygroup, arielalexisxrp, halogen atom or lower alkyl;

R5denotes a hydrogen atom or lower alkyl;

R10denotes cyano, C(O)or SIG11or 1H-1, 2, 3, 4-tetrazol-5-yl, 1-alkyl-1,2,3,4-tetrazol-5-yl;

R11denotes a hydrogen atom, a lower alkyl and the where R1denotes lower alkyl; R2denotes a hydrogen atom or halogen; R3denotes a hydrogen atom or halogen, or lower alkyl or SIG or6in which R6denotes lower alkyl or lower arylalkyl; R4denotes a hydrogen atom; R5denotes a hydrogen atom or lower alkyl; R10denotes a cyano, a radical C(O)OR11or 1H-1, 2, 3, 4-tetrazol-5-yl; R11denotes a hydrogen atom, lower alkyl, alkylcarboxylic, or pharmaceutically acceptable salt of this compound.

3. Connection on p. 2, where R1denotes an ethyl group; R2denotes a hydrogen atom, chlorine or fluorine; R3denotes a hydrogen atom, fluorine or chlorine, or a methyl group, a methoxy group or benzyloxy; R4denotes a hydrogen atom; R5denotes a hydrogen atom or lower alkyl; R10denotes a cyano, a radical C(O)OR11or 1H-1, 2, 3, 4-tetrazol-5-yl; R11denotes a hydrogen atom, lower alkyl, alkylcarboxylic, or pharmaceutically acceptable salt of this compound.

4. Connection at one PM.1-3, which is chosen among compounds of the following formulas:

tert-butyl 3-(9-benzyloxy-10-fluoro-4-oxo-4,6-dihydroindole-2-yl)-3-hydroxypentanal;

tert-butyl-3-hydroxy-3-(7-methyl-4-oxo-4, 6-dihydroindeno[1,2-b]quinoline-2-yl)pentanoate;

3-hydroxy-3-(4-oxo-4,6-dihydroindeno[1,2-b]-quinoline-2-yl)pentametric;

tert-butyl-3-hydroxy-3-(4-oxo-4,6-dihydroindeno-[1,2-b]quinoline-2-yl)pentanoate;

3-hydroxy-3-(4-oxo-4,6-dihydroindeno[1,2-b]-quinoline-2-yl)pentane acid;

3-(9-benzyloxy-10-fluoro-4-oxo-4,6-dihydroindole-[1, 2-b]quinoline-2-yl)-3-hydroxypentanal acid;

3-(10-fluoro-9-methoxy-4-oxo-4,6-dihydroindeno[1, 2-b]quinoline-2-yl)-3-hydroxypentanal acid;

3-hydroxy-3-(7-methyl-4-oxo-4,6-dihydroindeno[1, 2-b)quinoline-2-yl)pentane acid;

3-(9-benarasi-4-oxo-4,6-dihydroindeno[1, 2-b] - quinoline-2-yl)-3-hydroxypentanal acid;

3-(10-chloro-9-methyl-4-oxo-4,6-dihydroindole(1, 2-b] - quinoline-2-yl)-3-hydroxypentanal acid;

methyl-3-hydroxy-3-(4-oxo-4,6-dihydroindeno[1,2-b] - quinoline-2-yl)pentanoate;

tert-butylcarbamoyl-3-hydroxy-3-(4-oxo-4,6-dihydroindeno[1,2-b]quinoline-2-yl)pentanoate;

2-[1-hydroxy-1-(1H-1,2,3,4-tetrazol-5-ylmethyl)propyl]-4,6-dihydroquinoline[1,2-b]quinoline-4-one;

or pharmaceutically acceptable salt of these compounds.

5. Connection at one PM.1-4, which is a 3-hydroxy-3-(4-oxo-4,6-DuChene compounds of General formula (I), described in any of paragraphs.1-5, in which R10refers to a group C(O)OR11or 1-alkyl-1, 2, 3, 4-tetrazol-5-yl, where R11denotes a hydrogen atom, lower alkyl, alkylcarboxylic, characterized in that pyridine General formula And

in which R1has the meaning specified in paragraph 1, and the group Z1denotes lower alkyl, N-alkylate the quinoline General formula In

in which R2, R3, R4and R5shall have the meaning specified in paragraph 1, X denotes a chlorine atom, bromine or iodine and Y denotes or bromine atom, or hydroxyl group,

obtaining compounds of General formula

in which R1, R2, R3, R4, R5shall have the meaning specified in paragraph 1, and X and Z1have the above meaning,

then cyclist compound of General formula With obtaining compounds of General formula (I), as defined in paragraph 1, in which10denotes carbalkoxy, the compound obtained, if necessary, omelet with obtaining the compounds of formula (I) in which R10denotes a carboxy radical, which, if necessary, atrificial for obtaining compounds of formuls obtaining the compounds of formula (I), in which R10means other carbalkoxy radical.

7. The method of obtaining compounds of General formula (I), in which10denotes a cyano or 1H-1, 2, 3, 4-tetrazol-5-yl, wherein pyridine General formula D

in which R1has the meaning specified in paragraph 1, and Z2and Z3represent, independently, lower alkyl, or Z2and Z3together form a saturated hydrocarbon chain containing from 2 to 4 carbon atoms, N-alkylate the quinoline General formula defined in paragraph 6, to obtain the compounds of General formula E

in which R1, R2,R3, R4, R5shall have the meaning specified in paragraph 1, and X, Z2and Z3have the above meaning,

then cyclist compound of General formula E with obtaining compounds of General formula F

in which R1, R2, R3,R4, R5, Z2and Z3have the above meaning,

then release the protected carbonyl group of compounds of General formula F with obtaining compounds of General formula G

in which R1, R2, R3that is epoxidised agent with obtaining the compounds of formula N

in which R1, R2, R3, R4and R5shall have the meaning specified in paragraph 1,

then apachegroup compounds of General formula H handle tianyoude agent to obtain compounds of General formula (I), as defined in paragraph 1, in which R10denotes cyano, which, if necessary, is subjected to reaction bipolar connection with azide to obtain a compound of formula (I) in which R10means radical 1H-1, 2, 3, 4-tetrazol-5-yl.

8. The method of obtaining compounds of General formula (I), in which10refers to a group C(O)OR11or 1-alkyl-1, 2, 3, 4-tetrazol-5-yl, where R11denotes a hydrogen atom, lower alkyl, alkylcarboxylic, characterized in that pyridine General formula D

in which R1has the meaning specified in paragraph 1, and Z2and Z3represent, independently, lower alkyl, or Z2and Z3together form a saturated hydrocarbon chain containing from 2 to 4 carbon atoms, N-alkylate the quinoline General formula defined in paragraph 6, to obtain the compounds of General formula E

in which R1, R2, R3, R4, form a compound of General formula E with obtaining compounds of General formula F

in which R1, R2, R3, R4, R5, Z2and Z3shall have the meaning specified in paragraph 1,

then release the protected carbonyl group of compounds of the General formula F with obtaining compounds of General formula G

in which R1, R2, R3, R4and R5shall have the meaning specified in paragraph 1, which alkylate by a carbonyl group, using the appropriate alkylating agent to obtain the corresponding compounds of formula (I), the compound obtained of the formula (I) in which R10means a radical of carbalkoxy, if necessary, omelet with obtaining the compounds of formula (I) in which R10means carboxy radical, which then, if necessary, atrificial to obtain the compounds of formula (I), where R10means carbalkoxy, which, if necessary, praeteritorum to obtain the compounds of formula (I) in which R10- another carbalkoxy radical.

9. Compounds of General formula And

in which R1denotes lower alkyl,

and the group Z1denotes lower alkyl.

10. The method of obtaining compounds of General formula And sub>1denotes lower alkyl,

the group Z1denotes a lower alkyl group and Z2and Z3represent, independently, lower alkyl, or Z2and Z3together form a saturated hydrocarbon chain containing from 2 to 4 carbon atoms,

exempt from protection by obtaining pyridinone the General formula

in which R1has the meaning specified in paragraph (9,

then the compound of General formula To handle functionalized alkylating agent, resulting in a receive connection with the General formula a in which R1and Z1shall have the meaning specified in paragraph 9.

11. Compounds of General formula D

in which R1denotes lower alkyl,

and Z2and Z3represent, independently, lower alkyl, or Z2and Z3together form a saturated hydrocarbon chain containing from 2 to 4 carbon atoms.

12. The method of obtaining compounds of General formula D on p. 11, characterized in that ketogroup in the compound of General formula K, defined in paragraph 10, protects obtaining compounds of General formula D, in which R1, Z2and Z3have the meanings specified in paragraph 11.

13. Compounds of General fo what about any of paragraphs.1-5 or its pharmaceutically acceptable salt as anticancer drugs.

15. Pharmaceutical composition having inhibitory activity against topoisomerase I and II, containing as active principle at least one of the compounds according to any one of paragraphs.1-5.

16. Compounds according to any one of paragraphs.1-5 to obtain drugs for inhibition of topoisomerases type I or type II topoisomerases, or both topoisomerases both types.

 

Same patents:

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 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

--carboline" target="_blank">

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

The invention relates to the field of organic chemistry, namely to new bicyclic derivative

The invention relates to new derivatives oksiminoalkil acid of the formula (I), where R1is oxazolyl, optionally substituted with 1-2 substituents selected from lower alkyl, phenyl, teinila, furil; thiazolyl, optionally substituted with 1-2 substituents selected from lower alkyl, phenyl; unsubstituted chinoline and so on; X represents a bond or the group-NR6- where R6represents hydrogen or C1-4alkyl; n represents an integer from 1 to 3; Y represents an oxygen atom or the group-NR7- where R7is hydrogen; ring a represents a benzene ring, optionally substituted by one or two1-4alkoxy; p is an integer from 1 to 3; R2represents phenyl, optionally substituted lower alkyl, halogen, and so on; unsubstituted furyl; unsubstituted pyridyl; pyridinyl-1-oxide; q is an integer from 0 to 6; m represents 0 or 1; R3represents a hydroxy-group, lower alkoxy or-NR9R10where R9and R10represent identical or different groups selected from hydrogen, lower alkyl and lower alkylsulfonyl; R4and R5represent identical or different groups selected from hydrogen or

The invention relates to tetrahydro-gamma carbolines formula (I), where R1, R2D, Alk and n are such as defined in the claims

The invention relates to a derivative of tetrahydroimidazo[2,1-a]isoquinoline of the formula (I), where X represents a group (A) or (B), R1, R2and R3are hydrogen, C1-6by alkyl or halogen, a R4, R5, R6and R7are hydrogen

The invention relates to a new 1.8-fused derivative of 2-Hinayana formula (I), where A, X, R1, R2, R3, R4, R5, R6such as defined in the claims

-converting enzyme)" target="_blank">

The invention relates to novel ortho-sulfonamidophenylhydrazine heteroaryl hydroxamic acids of the formula

< / BR>
where W and X are both carbon, T is nitrogen, U represents CR1where R1represents hydrogen, or alkyl containing 1-8 carbon atoms, R represents-N(CH2R5)-SO2Z, Q represents -(C=O)-NHOH, with

< / BR>
is a benzene ring, or is a heteroaryl ring of 5 to 6 atoms in the cycle, which may contain 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the heteroatom of nitrogen, denoted as W, where benzene or heteroaryl ring may optionally contain one or two substituent R1where permissible; Z is phenyl, which is optionally substituted by phenyl, alkyl with 1-8 carbon atoms, or a group OR2; R1represents halogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, perfluoroalkyl from 1 to 4 carbon atoms, phenyl, optionally substituted by 1-2 groups OR2group-NO2group -(CH2)nZ, where Z is a phenyl which allows an alkyl with 1-8 carbon atoms, phenyl, optionally substituted with halogen, or heteroaryl radical containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; R5represents hydrogen, alkyl with 1-8 carbon atoms, phenyl, or heteroaryl containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; or their pharmaceutically acceptable salts
Up!