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1. WO1997029110 - THIOPHENOPYRIMIDINES

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[ EN ]

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;
RUs NR^ or ORS;
R2 is C i _6alkyl , C | _6alky loxy or C i .^alkylthio;
R3 is hydrogen,
Cj-galkylsulfonyl,

R4 is hydrogen, CMalkyl, mono- or di(C3-6cycloalkyl)methyl, C3_6cycloalkyl,
C3-6alkenyl, hydroxyCi^alkyl, Ci.6alkylcarbonyloxyCi_6a.kyl or
C i .βalky loxyC j ^alkyl ;
R5 is C galkyl, mono- or di(C3-6cycloalkyl)methyl, AτlCU2, C3-6alkenyl,
C^alkyloxyCi^alkyl, hydroxyCi-6alkyl, thieny lmethyl, furanylmethyl,
Cι.6alkylthioCι.6alkyl, morpholinyl, mono- or di(Cι.6alkyl)aminoCι_6alkyl, di(Cι-6alkyl)amino, Cι.6alkylcarbonylCι.6alkyl, Cι.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 Ci^alkyl or Ci.galkyloxyCi.βalkyl;
Ar is phenyl; phenyl substituted with 1, 2 or 3 substituents independently selected from halo,

benzyloxy, C\ ^alkylthio, nitro, amino and mono- or di(Ci-6alkyl)amino;
pyridinyl; pyridinyl substituted with 1, 2 or 3 substituents independently
selected from halo,
trifluoromethyl, hydroxy, cyano,

benzyloxy,
nitro, amino, mono- or di(Cι.6alkyl)amino and
piperidinyl; and wherein said substituted phenyl may optionally be further
substituted with one or more halogens;
Ar1 is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently
selected from halo, Ci^alkyl, C ^alkyloxy, di(Cι.6alkyl)aminoCι_6alkyl
trifluoromethyl, and Cι_6alkyl substituted with morpholinyl; or pyridinyl; and Alk is Ci.βalkanediyl.

2. A compound according to claim 1 wherein R1 is OR5 and R5 is Ci^alkyl; or R1 is NR4R5 and R4 is hydrogen,
and R5 is
CMalkyl, hydroxyCi^alkyl, C3.6alkenyl or C3.6cycloalkylmethyl; or R1 is NR4R5 and 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 Cι. alkyl or Cι.6 lkyloxyCι. alkyl; R2 is
R3 is hydrogen or CMalkyl; and Ar is a phenyl substituted with 1, 2 or 3 substituents each independently selected from Cj-βalkyl,
or halo, or Ar is a pyridinyl substituted with 1 , 2 or 3 substituents each independently selected from C i -6alk 1 or di(C j . alky l)amino.

3. A compound according to any of claims 1 to 2 wherein R1 is NR4R5 wherein R4 is C2-4alkyl or methoxy C1.2alk.yl; R5 is C2-4alkyl, cyclopropylmethyl or hydroxy- C2-4alkyl; R2 is Cι.2alkyl; R3 is hydrogen or CMalkyl.

A compound according to any of claims 1 to 2 wherein Rl is NR R5 wherein R4 is C2-4alkyl; 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-dipropylarnino)-8-(2,4,6-trimethylphenyl)- thiopheno[3,2-d]pyrimidine; the stereochemically isomeric forms, or the pharmaceutically acceptable acid addition salts thereof.

6. A composition comprising a pharmaceutically acceptable carrier, and as active ingredient 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 1 to 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 (II1) wherein the radicals R2, R3 and Ar are as defined in any of claims 1 to 4 and radical is hydroxy, halo, mesyloxy or tosyloxy; a stereoisomeric form or an acid addition salt form thereof.


10. A process of preparing a compound as claimed in claim 1 , characterized bv 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 R1 is

OR5,


wherein in the above reaction schemes the radicals R1 , R2, R3, R5 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 art- known 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 stereoche ically isomeric forms thereof.

1. 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;



(VIII) (II'-b) (II-a)

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.