Derivatives epothilone and methods for their preparation, pharmaceutical composition and method of treatment based on them

 

The invention relates to new derivatives epothilone formula I, where the bond indicated by a wavy line indicates that the bond “a” is either CIS-or TRANS-form; (I) R2absent or represents oxygen; “a” denotes a single or double bond; “b” is absent or represents a simple bond; and “C” is absent or represents a simple bond, provided that when R2denotes oxygen, then “b” and “C” both represent a simple bond and a represents a simple bond; if R2no, the “b” and “C” both are absent and “a” represents a double bond; and if “a” represents a double bond, R2“b” and “C” are absent; R3denotes a radical selected from the group comprising hydrogen; (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; -CH2-OH; R4and R5independently of one another denote hydrogen; R1denotes a radical of the structure (a-d); (II) if R3means (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; CH2-HE; and other symbols except for the R1matter, the decree is ub>-HE; and other symbols except for the R1have the above values, R1can also represent a fragment of formula (j); or a salt of the compounds of formula I, if there is a salt-forming group. Pharmaceutical composition having a proliferative effect, containing a compound of formula I and a pharmaceutically acceptable carrier. The method of obtaining the compounds of formula I, including the interaction of iodide of the formula II, where R2, R3, R4, R5, a, b and C and denoted by a wavy line bond shall have the meanings indicated above with a tin-containing compound of the formula R1-Sn(R)3where R1has the values given above and R stands for (ness.)alkyl, methyl or n-butyl. The method of obtaining the compounds of formula I, including the interaction of tin-containing compounds of the formula IV with iodide of the formula R1-I, and, if necessary, conversion of the resulting compound of formula I into another compound of the formula I, converting the resulting free compounds of formula I in salt of the compounds of formula I and/or conversion of the resulting salts of the compounds of formula I into the free compound of formula I or into another salt of the compound of formula 1, and/or separating a mixture of stereoisomers of compounds potigny action. 8 c. and 10 C.p. f-crystals, 3 PL.

Description text in facsimile form (see graphic part).

Claims

1. Derivatives epothilone formula I

where connection is indicated by a wavy line indicates that the link is either CIS-or TRANS-form;

(I) R2absent or represents oxygen; and denotes a single or double bond; b is absent or represents a simple bond; C is absent or represents a simple bond, provided that when R2denotes oxygen, then b and C both represent a simple bond and a represents a simple bond; if R2missing, b and C are absent and a denotes a double bond; if a denotes a double bond, R2, b and C are absent;

R3denotes a radical selected from the group comprising hydrogen,

(ness.)alkyl, -CH2F, -CH2-HE;

R4and R5independently of one another denote hydrogen;

R1denotes a radical selected from radicals having the following structure:

(II) if R3means (ness.)alkyl, especially meta characters with the exception of R1have the above values, R1may also denote a radical selected from radicals having the following structure:

(III) if R3denotes-CH2-HE; and other symbols except for the R1have the above values, R1may also denote a radical of the formula

or salt of the compounds of formula I, if there is a salt-forming group.

2. The compound of formula I under item 1, where R2absent or represents oxygen; and indicates either simple or double bond; b is absent or represents a simple bond; C is absent or represents a simple bond, provided that when R2denotes oxygen, then b and C both represent a simple bond and a represents a simple bond; if R2missing, b and C are absent and a denotes a double bond; and if a denotes a double bond, R2, b and C are absent; R3denotes a radical selected from the group comprising hydrogen,

(ness.)alkyl, -CH2F, -CH2-OH; R4and R5independently of one another denote hydrogen; R1denotes the radical, vibronically soleobrazutaya group.

3. The compound of formula I under item 1, where R2absent or represents oxygen; and indicates either simple or double bond; b is absent or represents a simple bond; C is absent or represents a simple bond, provided that when R2denotes oxygen, then b and C both represent a simple bond and a represents a simple bond; if R2missing, b and C are absent and a denotes a double bond; and if a denotes a double bond, R2, b and C are absent; R3denotes a radical selected from the group comprising hydrogen, (ness.)alkyl, -CH2F, -CH2-OH; R4and R5independently of one another denote hydrogen; and

R1denotes a radical selected from the group of radicals having the following structure:

or its salt, if salt-forming group.

4. The compound of formula I under item 1, where R2absent or represents oxygen; and indicates either simple or double bond; b is absent or represents a simple bond; C is absent or represents a simple bond, provided that when R2denotes oxygen, then b and C both represent a simple bond and a represents a simple bond; if R2 b and C are absent; R3denotes a radical selected from the group comprising (ness.)alkyl, -CH2F; CH2-HE;

R4and R5independently of one another denote hydrogen; and R1denotes a radical selected from the group of radicals having the following structure:

or its salt, if present, one or more salt-forming groups.

5. The compound of formula I under item 1, where R2absent or represents oxygen; and indicates either simple or double bond; b is absent or represents a simple bond; C is absent or represents a simple bond, provided that when R2denotes oxygen, then b and C both represent a simple bond and a represents a simple bond; if R2missing, b and C are absent and a denotes a double bond; and if a denotes a double bond, R2, b and C are absent; R3denotes a radical selected from the group comprising (ness.)alkyl other than methyl, -CH2F, -CH2-OH; R4and R5independently of one another denote hydrogen; R1denotes a radical of the formula

6. Connection on p. 1 of formula IC

where And denotes ethyl, vermeil, methoxy, methylthio or ethynyl (-CH=CH2);

D represents hydrogen, fluorine, hydroxy or methyl.

8. Connection on p. 1 of the formula S

where And denotes ethyl, vermeil, methoxy, methylthio or ethynyl (-CH=CH2);

D represents hydrogen, fluorine, hydroxy or methyl.

9. Connection on p. 1, selected from the group comprising compounds of the following formulas:

10. Connection on p. 1 the following formula:

or its pharmaceutically acceptable salt, if salt-forming group.

11. Pharmaceutical composition having proliferative activity, comprising a compound according to any one of paragraphs.1-10 and a pharmaceutically acceptable carrier.

12. The compound according to any one of paragraphs.1-10, intended for the treatment of proliferative diseases.

13. A method of treating a warm-blooded animal suffering from a proliferative disease and in need of such treatment, introducing a warm-blooded animal a compound of formula I or its pharmaceutically acceptable salt according to p. 1 in sufficient quantity for such treatment.

14. Pharmaceutical composition suitable for administration warm-blooded animal for the treatment of proliferative diseases, including the number of the active substance of the formula I on p. 1, effective for the treatment of the said proliferative disease, together with at least one pharmaceutically acceptable carrier.

15. The method of obtaining the compounds of formula I on p. 1, including the interaction of iodide of the formula II

where R

where R1has the values specified for formula I, and R denotes (ness.)alkyl, especially methyl or n-butyl.

16. The method of obtaining the compounds of formula I on p. 1, including the interaction of tin-containing compounds of the formula IV

where R2, R3, R4, R5, a, b and C and denoted by a wavy line bond shall have the meanings specified for formula I, with iodide of the formula V

where R1has the values specified for formula I, in paragraph 1,

and, if necessary, conversion of the resulting compound of formula I into another compound of the formula I, converting the resulting free compounds of formula I in salt of the compounds of formula I and/or conversion of the resulting salts of the compounds of formula I into the free compound of formula I or into another salt of the compounds of formula I, and/or separating a mixture of stereoisomers of the compounds of formula I to the corresponding isomers.

17. The method of obtaining the compounds of formula VI

characterized in that the compound of formula VII

where R3denotes (.)�085.gif">

18. The method of obtaining epothilones E or F of the formula IX

where Q denotes hydrogen or methyl, characterized in that the compound of the formula X

where Q denotes hydrogen or methyl, epoxidized in the presence of the epoxide with obtaining the compounds of formula IX.

 

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