Hintline inhibiting farnesyltransferase

 

The proposed derivatives of hintlian General formula (I) and their pharmaceutically acceptable acid additive salt and stereochemical isomeric forms, where the dotted line is an optional bond; X is oxygen; R1and R2each independently are hydrogen or halogen; R3and R4each independently are hydrogen or halogen; R5is hydrogen, halogen or a radical of the formula-O-R10(a-1) or N-R11R12(a-3), where R10, R11and R12are hydrogen; R6is a radical of formula (b-1) or (b-2), where R16is hydrogen or phenyl; R17is hydrogen or C1-6by alkyl; R7is hydrogen or C1-6the alkyl, provided that the dotted line is not a bond; R8is hydrogen, C1-6the alkyl or Het1CH2; R9is hydrogen; Het1is pyridinyl. Compounds of General formula (I) have inhibitory farnesyltransferase activity and can be used to obtain drugs, inhibiting proliferative diseases. The objects of the invention are also pharmaceutical composition having ingibirujut the intermediate derivatives of hintlian General formula (IX) and their acid additive salt or a stereochemical isomeric forms, in which n is 2 or 3 and R1, R2, R3, R4and R9have the meanings defined above; a method of obtaining representatives of compounds of General formula (I), where R6is a radical of formula (b-2), and the method for intermediate derivatives of hintlian General formula (XI) and their acid additive salt or a stereochemical isomeric forms. 6 C. and 4 h.p. f-crystals, 4 PL.

Description text in facsimile form (see graphic part). The

Claims

1. Derivatives of hintlian General formula (I)and their pharmaceutically acceptable acid additive salt and stereochemical isomeric forms, where the dotted line is an optional bond; X is oxygen; R1and R2each independently is hydrogen or halogen;
R3and R4each independently is hydrogen or halogen;
R5is hydrogen, halogen or a radical of the formula
-O-R10(a-1);
-N-R11R12(a-3),
where R10, R11and R12�mg_data/60/604187.gif">
where R16is hydrogen or phenyl;
R17is hydrogen or C1-C6by alkyl;
R7is hydrogen or C1-C6the alkyl, provided that the dotted line is not a bond;
R8is hydrogen, C1-C6the alkyl or Het1CH2;
R9is hydrogen;
Het1is pyridinyl.

2. Connection on p. 1, in which R1and R2each independently selected from hydrogen, halogen; R3and R4each independently selected from hydrogen, halogen; R5is hydrogen, hydroxy, halogen or amino; R6is a radical of formula (b-1) or (b-2), where R16is hydrogen and R17is1-C4by alkyl; R7is hydrogen or C1-C4the alkyl, if the dotted line is not a bond; R is hydrogen, C1-C4the alkyl or Het1CH2; R9is hydrogen.

3. The compound according to any one of paragraphs.1-3, in which X is oxygen; R1is 3-chloro; R2is hydrogen; R3is 4-chloro; R4is hydrogen; R5is hydrogen; halogen or amino; R6is Radik is up> is hydrogen or C1-C2the alkyl, if the dotted line is not a bond; R8is hydrogen, C1-C2the alkyl or Het1CH2; and R9is hydrogen.

4. Connection on p. 1, representing
6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl] -4-(3-chlorophenyl)-1-methyl-2-(1H)-hintline or
6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl] -4-(3-chlorophenyl)3,4-dihydro-1,3-dimethyl-2-(1H)-hintline,
its stereoisomeric forms or pharmaceutically acceptable acid additive salt.

5. 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.1-4.

6. The method of obtaining pharmaceutical compositions under item 5, in which a therapeutically active amount of the compound according to any one of paragraphs.1-4 thoroughly mixed with a pharmaceutically acceptable carrier.

7. Derivatives of hintlian General formula (XI)

their acid additive salt or a stereochemical isomeric form, where n is 2 or 3 and R1, R2, R3, R4and R9aktivnosti.

9. The method of obtaining derivatives of hintlian formula (I) under item 1, or pharmaceutically acceptable acid additive salts, or their stereochemical isomeric forms, where the dashed line and the radicals X, R1, R2, R3, R4and R5have the meanings given in paragraph 1, and R6is a radical (b-2 defined in paragraph 1, including the interaction of the intermediate ketone of formula (VI)

with an intermediate compound of the formula


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 obtaining the compounds of formula


where the dashed line and the radicals X, R1, R2, R3, R4, R7, R8, R9and R16defined in paragraph 1,
followed, if necessary, restoration of the compounds of formula (Ib-1) or (Ib-2) obtaining videopreteen compounds of formula (I), where R5is hydrogen, or halogenoalkanes obtained compounds of the formula (Ib-1) or (Ib-2) obtaining videopreteen is their compounds in videopreteen the compounds of formula (I), where R5represents a group (a-3) specified in paragraph 1 and, if necessary, videopreteen the compounds of formula (I), where the dotted line is a bond, restore obtaining the compounds of formula (I) where this connection is absent, or, on the contrary, videopreteen the compounds of formula (I), where the dotted line is not a link, oxidized with getting videopreteen compounds of formula (I), where the dotted line is a bond or videopreteen the compounds of formula (I), where R7is hydrogen, is treated with a reagent R7W1where W1is a suitable leaving group and R7is C1-C6the alkyl, provided that the dotted line is no bond and/or, if desired, the resulting compound of formula (I) converted into pharmaceutically acceptable acid additive salt, or conversely, an acid additive salt of the compounds of formula (I) is transformed into the free base by means of alkali and, if desired, receive their stereochemical isomeric form.

10. The method of obtaining the compounds of formula (XI) under item 7

where n is 2 or 3 and R1, R2, R3, R4and R9defined in paragraph 1,
including cyclization of promezhutochnoye, and, if necessary, the compounds of formula (XI) is converted into an acid additive salt, or conversely, an acid additive salt of the compounds of formula (XI) is converted into the free base by means of alkali and, if desired, receive their stereochemical isomeric form.

 

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