Tetrahydroquinoline derivatives and the use thereof for the treatment of cancer
AssigneeMerck Patent GmbH
InventorsKai Schiemann, Dirk Finsinger, Christiane Amendt, Frank Zenke
Life of this patent
Estimating the term…
Abstract
Compounds of the formula (I), in which E, R3, R4, R5, X, Y, W, Q1, Q2, Z, s and m have the meanings indicated in claim 1, can be employed, inter alia, for the treatment of tumours.
Claims24
Compounds of the formula I
- in which
- E denotes
- X denotes O, NR or S,
- R1, R2, independently of one another, denote H, A, Hal, SA, (CH2)pCN, SCN, (CF2)pCF3, SF5, OA, O(CF2)pCF3, S(CF2)pCF3, NR2, NRCOR, NRSO2R, NR(CH2)pNR2, CONR(CH2)pNR2, SO2NR(CH2)pNR2, CONR2, SO2NR2, COOR,
- R3 denotes H, A
- A denotes linear or branched alkyl having 1 to 10 C atoms or cycloalkyl having 3 to 7 C atoms,
- R4 denotes aryl or heteroaryl, each of which is unsubstituted or mono- or polysubstituted by aryl or heteroaryl, each of which may be substituted by Hal, NO2, CN, A, OR, OCOR, NR2, CF3, OCF3, OCH(CF3)2, or by Hal, NO2, CN, OR, A, —(CY2)n—OR, —OCOR, —(CY2)n—CO2R, —(CY2)n—CN or (CY2)n—NR2,
- Y denotes H, A, Hal, OR
- R denotes H, A, (CH2)pO(CH2)pR3, (CH2)pNA(CH2)pR3,
- W denotes CH2, C═O, C═S or a single bond,
- Q1 denotes NR, O, S or a single bond,
- Z denotes —SO2—, —SO—, CO, CS,
- or a single bond,
- Q2 denotes NR, S, O or a single bond,
- R5 denotes H, (CY2)pNR2, (CY2)pOR,
- (CY2)pSR,
- (CY2)pQ1COQ1R, (CY2)pCOOR and, if Q2 denotes a single bond, also Hal,
- Hal denotes F, Br or Cl
- n denotes 1, 2, 3 or 4,
- m denotes 0, 1 or 2
- p denotes 0, 1, 2, 3, 4, 5, 6, 7 or 8 and
- denotes 0, 1 or 2,
- and pharmaceutically usable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.
Compounds of the sub-formulae IA to ID:
- Y, W, Q1, Q2, Z, R, R2 R4, R5 and n have the meanings indicated above.
Process for the preparation of compounds of the formula I and pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers thereof, characterised in that compounds of the formula II selected from the following group:
- in which R1, R2 and R have the meanings indicated above,
- are reacted with a compound of the formula III
- in which
- R4 has the meaning indicated above, and
- with a compound of the formula IV
- in which X and s have the meanings indicated above,
- preferably in the presence of a protonic acid or Lewis acid, such as, for example, trifluoroacetic acid, hexafluoroisopropanol, bismuth (III) chloride, ytterbium(III) triflate, scandium (III) triflate or ammonium cerium (IV) nitrate,
- and a radical other than H is optionally introduced by conventional methods for R3 and/or a base or acid of the formula I is optionally converted into one of its salts.
A mixture comprising one or more compounds of the formula I and amount of one or more compounds of the formula V, analogues thereof and/or metabolites thereof,
- in which
- Y′ and Z′ each, independently of one another, denote O or N, R9 and R10 each, independently of one another, denote H, OH, halogen, OC1-10-alkyl, OCF3, NO2 or NH2, s′ denotes an integer between 2 and 6, each inclusive, and R8 and R11 are each, independently of one another, in the meta- or para-position and are selected from the group:
Dependencies are inferred from the claim text.