1,8-kannelirovannye derivative of hinayana, substituted n - or c-linked imidazoles that inhibit farnesyltransferase

 

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. Also described is a method of obtaining the proposed compounds, pharmaceutical composition having inhibitory farnesyltransferase activity, and how you can get it. Also disclosed are intermediate compounds suitable for the manufacture of the proposed compounds and methods for their preparation. The invention can be used in medicine as a therapeutic agent. 8 C. and 3 h.p. f-crystals, 7 PL.

Table T%

Claims

1. 1,8-Kannelirovannye derivative of Hinayana General formula (I)its pharmaceutically acceptable acid additive salt or a stereochemical isomeric form, where the dotted line is an optional bond; X is oxygen or sulfur; -A - is a bivalent radical of formula-CH= CH- (a-1); -CH2-CH2- (a-2); -CH2-CH2-CH2- (and-3); -CH2-O- (a-4); -CH2-CH2-O- (a-5); -CH= N- (a-8); -N= N- (a-9) or-CO-NH- (a-10), where there is each independently is hydrogen, halogen, C1-C6by alkyl; R3and R4each independently is hydrogen, halogen, C1-C6the alkyl, C1-C6alkyloxy; R5is a radical of the formula


where R13is hydrogen;
R14is C1-C6by alkyl;
R6is hydrogen, hydroxy, halogen or a radical of the formula-N-R8R9where R8and R9are hydrogen.

2. Connection on p. 1, in which X is oxygen; the dotted line is a bond, R1the 3-halogen; R2is hydrogen; R3is 4-halogen; R4is hydrogen; R5is a radical of formula (d-l), where R13is hydrogen or R5is a radical of formula (d-2) in which R13is hydrogen and R14is C1-C6by alkyl; R6is hydrogen, halogen, hydroxy or amino; and-As - is (a-1), (a-2) or (a-3).

3. Connection on p. 1, which is selected from
7-(3-chlorophenyl)-9-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl] -2,3-dihydro-1H, 5H-benzo[ij] chinolin-5-it,
7-(3-chlorophenyl)-9-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl] -1,2-dihydro-4H-Pirro[3,2,1-ij] quinoline-4-it; or
8-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl] -6-(3-chlorophenyl)-2,3-dihydro-1H, 5H-benzo[ij] chinolin-5-it;
their stereoisomeric forms or pharmaceutically acceptable acid additive salts.

4. Pharmaceutical composition having inhibitory farnesyltransferase activity, including pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to any one of paragraphs. 1-3.

5. A method of obtaining a pharmaceutical composition according to p. 4, in which a therapeutically effective amount of a compound according to any one of paragraphs. 1-3 thoroughly mixed with a pharmaceutically acceptable carrier.

6. The compound of formula (VI)

the acid additive salt or a stereochemical isomeric form, where X, R1, R2and-As - such, as defined in paragraph 1.

7. The compound of formula (II)

its pharmaceutically acceptable acid additive salt or a stereochemical isomeric forms,
where the dotted line is an optional bond;
X, R1, R2, R3, R4and-As - such, as defined in paragraph 1.

8. The compound according to any one of paragraphs. 1-3 for use as Les the formula (II)

where R1, R2, R3, R4X and-And - take of the values defined in paragraph 1;
subjected to interaction with an intermediate compound of formula (III-1) or (III-2)


where R13takes the values defined in paragraph 1;
in the presence of a suitable strong base and in the presence of a suitable derivative of silane, optionally with subsequent removal of the protective group PG, to obtain the compound (I-a-1) or (I-a-2), respectively:


where R1, R2, R3, R4, R13X and-And - take of the values defined in paragraph 1;
and, further, if necessary, the compounds of formula (I-a), defined as compounds of formula (I) in which R6is hydroxy, converted into the compounds of formula (I-C), in which R6is halogen,

where R1, R2, R3, R4, R5X and-And - take of the values defined in paragraph 1;
optionally followed by treatment of the intermediate compound of formula H-NR8R9obtaining compounds of formula (I-d)

10. The method of obtaining the compounds of formula (VI) under item 6, in which the intermediate compound of formula (IV)

where X, R1, R2and-And - take of the values defined in paragraph 1,
cyclist in the presence of polyphosphoric acid (PFC), and, if desired, the compound of formula (VI) is converted into pharmaceutically acceptable acid additive salt, or conversely, an acid additive salt of the compounds of formula (VI) is converted into the free base with alkali; and, if desirable, get their stereochemical isomeric form.

11. The way to obtain the intermediate compounds of formula (II) under item 7, in which the intermediate compound of formula (VI)

process the intermediate compound of formula (V)

in the presence of polyphosphoric acid (PFC) to obtain the compounds of formula (II-a)

and, dgla (II) in which the dotted line is not a bond, can be converted into intermediate compounds of formula (II-b), defined as compounds of formula (II) in which the dotted line represents a relationship, oxidation

where X, R1, R2, R3, R4and-And - take of the values defined in paragraph 1;
and, if desirable, the compound of formula (II) converted into pharmaceutically acceptable acid additive salt, or conversely, an acid additive salt of the compounds of formula (II) is transformed into the free base by means of alkali and, if desired, receive their stereochemical isomeric form.

 

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< / BR>
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