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1. CA2233307 - THIOPHENOPYRIMIDINES

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Claims
1. A compound of formula
including the stereoisomers and the pharmaceutically acceptable acid addition salt forms thereof, wherein
X is S, SO or SO2;
R1 is NR4R5 or OR5;
R2 is C1-6alkyl, C1-6alkyloxy or C1-6alkylthio;
R3 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl, C1-6alkylsulfoxy or C1-6alkylthio;R4 is hydrogen, C1-6alkyl, mono- or di(C3-6cycloalkyl)methyl, C3-6cycloalkyl,
C3-6alkenyl, hydroxyC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl or
C1-6alkyloxyC1-6alkyl;
R5 is C1-8alkyl, mono- or di(C3-6cycloalkyl)methyl, Ar1CH2, C3-6alkenyl,
C1-6alkyloxyC1-6alkyl, hydroxyC1-6alkyl, thienylmethyl, furanylmethyl,
C1-6alkylthioC1-6alkyl, morpholinyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, di(C1-6alkyl)amino, C1-6alkylcarbonylC1-6alkyl, C1-6alkyl substituted with imidazolyl; or a radical of formula -Alk-O-CO-Ar1; or R4 and R5 taken together with the nitrogen atom to which they are attached may form a pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl group, optionally substituted with C1-6alkyl or C1-6alkyloxyC1-6alkyl;
Ar is phenyl; phenyl substituted with 1, 2 or 3 substituents independently selected from halo, C1-6alkyl, trifluoromethyl, hydroxy, cyano, C1-6alkyloxy, benzyloxy, C1-6alkylthio, nitro, amino and mono- or di(C1-6alkyl3amino; pyridinyl; pyridinyl substituted with 1, 2 or 3 substituents independently selected from halo, C1-6alkyl, trifluoromethyl, hydroxy, cyano, C1-6alkyloxy, benzyloxy, C1-6alkylthio, nitro, amino, mono- or di(C1-6alkyl)amino and piperidinyl; and wherein said substituted phenyl may optionally be further substituted with one or more halogens;
Arl is phenyl; phenyl substituted with 1, 2 or 3 substituents each independentlyselected from halo, C1-6alkyl, C1-6alkyloxy, di(C1-6alkyl)aminoC1-6alkyl trifluoromethyl, and C1-6alkyl substituted with morpholinyl; or pyridinyl; and
Alk is C1-6alkanediyl.
2. A compound according to claim 1 wherein R1 is OR5 and R5 is C1-6alkyl; or R1 is
NR4R5 and R4 is hydrogen, C1-6alkyl or C1-6alkyloxyC1-6alkyl, and R5 is
C1-6alkyl, hydroxyC1-6alkyl, C3-6alkenyl or C3-6cycloalkylmethyl; or R1 is NR4R5and R4 and R5 are taken together with the nitrogen atom to which they are attached to form a pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl group; optionally substituted with C1-6alkyl or C1-6alkyloxyC1-6alkyl; R2 is C1-6alkyl; R3 is hydrogen or C1-6alkyl; and Ar is a phenyl substituted with 1, 2 or 3 substituents each independently selected from C1-6alkyl, C1-6alkyloxy or halo, or Ar is a pyridinyl substituted with 1, 2 or 3 substituents each independently selected from
C1-6alkyl or di(C1-6alkyl)amino.
3. A compound according to any of claims 1 to 2 wherein R1 is NR4R5 wherein R4 is
C2-alkyl or methoxyC1-2alkyl; R5 is C2-4alkyl, cyclopropylmethyl or hydroxy-C2-4alkyl; R2 is C1-2alkyl; R3 is hydrogen or C1-2alkyl.
4. A compound according to any of claims 1 to 2 wherein R1 is NR4R5 wherein R4 is
C2-alkyl; R5 is C3-4alkyl or cyclopropylmethyl; R2 is methyl; R3 is hydrogen or methyl; and Ar is 3-pyridinyl substituted on the 4- and/or 6-position with methyl or dimethylamino.
5. A compound according to claim 1 wherein the compound is 2-methyl-6-(N-propyl-N-cyclopropylamino)-8-(2,4,6-trimethylphenyl)thiopheno[3,2-d]pyrimidine, and 2-methyl-6-(N,N-dipropylamino)-8-(2,4,6-trimethylphenyl)thiophenor3,2-d]pyrimidine; the stereochemically isomeric forms, or the pharmaceutically acceptable acid addition salts thereof.
6. A composition comprising a pharmaceutically acceptable carrier, and as activeingredient a therapeutically effective amount of a compound as claimed in any one of claims 1 to 5.
7. A process for preparing a composition as claimed in claim 6 characterized in that a therapeutically effective amount of a compound as claimed in any one of claims 1to 5 is intimately mixed with a pharmaceutically acceptable carrier.
8. A compound according to any one of claims 1 to 5 for use as a medicine.
9. A compound of formula (II'-a) wherein the radicals R2, R3 and Ar are as defined in any of claims 1 to 4 and radical W' is hydroxy, halo, mesyloxy or tosyloxy; a stereoisomeric form or an acid addition salt form thereof; with the proviso that2-methyl-7-phenyl-thieno[3,2-d]pyrimidin-4(1H)-one is not included.
10. A process of preparing a compound as claimed in claim 1, characterized by a) reacting an intermediate of formula (II) with an intermediate of formula (III) in a reaction-inert solvent,
b) O-alkylating an intermediate of formula (IX) with an intermediate of formula (X) in a reaction-inert solvent and in the presence of a suitable base, yielding compounds of formula (I-a), defined as compounds of formula (I) wherein Rl is
OR5,
wherein in the above reaction schemes the radicals R1, R2, R3, RS and Ar are as defined in claim 1 and W is an appropriate leaving group; or, if desired, converting compounds of formula (I) into each other following artknown transformation reactions; and further, if desired, converting the compounds of formula (I), into an acid addition salt by treatment with an acid, or conversely, converting the acid addition salt form into the free base by treatment with alkali; and, if desired, preparing stereochemically isomeric forms thereof.
11. A process of preparing a compound of formula (II'-a) as claimed in claim 9, characterized by cyclizing an intermediate of formula (VIII), thereby yielding intermediates of formula (II'-b), defined as compounds of formula (II'-a) wherein W' is hydroxy; and optionally converting compounds of formula (II'-b) into compounds of formula(II-a), defined as compounds of formula (II'-a) wherein W' is other than hydroxy; wherein in the above reaction schemes the radicals R2, R3 and Ar are as defined in any of claims 1 to 4, W' is hydroxy, halo, mesyloxy or tosyloxy and W is halo, mesyloxy or tosyloxy; or, if desired, converting compounds of formula (II'-a) into each other following art-known transformation reactions; and further, if desired, converting the compounds of formula (II'-a), into an acid addition salt by treatment with an acid, or conversely, converting the acid addition salt form into the free base by treatment with alkali; and, if desired, preparing stereochemically isomeric forms thereof.