Claims
- 1. A compound of formula ##STR127## a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein:
- R.sup.1 represents hydrogen, hydroxy, C.sub.1-6 alkyl or aryl;
- R.sup.2 represents hydrogen; C.sub.1-12 alkyl; C.sub.3-7 cycloalkyl; C.sub.2-8 alkenyl; aryl; pyrrolidinyl optionally substituted with C.sub.1-4 alkyl or C.sub.1-4 alkyloxycarbonyl; or C.sub.1-12 alkyl substituted with one or two substituents selected from C.sub.3-7 cycloalkyl, hydroxy, C.sub.1-4 alkyloxy, cyano, amino, mono- and di(C.sub.1-4 alkyl)amino, mono- and di(aryl)amino, arylC.sub.1-4 alkylamino, (C.sub.1-4 alkyl) (arylC.sub.1-4 alkyl)amino, pyrrolidinyl, piperidinyl, piperazinyl optionally substituted with C.sub.1-4 alkyl, morpholinyl, perhydro-azepinyl, carboxyl, C.sub.1-4 alkyloxycarbonyl, aminocarbonyl, mono- and di(C.sub.1-4 alkyl)aminocarbonyl, aryl, aryloxy and arylthio;
- R.sup.3 represents hydrogen, C.sub.1-6 alkyl, aryl or C.sub.1-6 alkyl substituted with aryl;
- Het represents an unsaturated heterocycle selected from imidazolyl, triazolyl, and tetrazolyl; each of said unsaturated heterocycles may optionally be substituted with amino, mercapto, C.sub.1-6 alkyl, C.sub.1-6 alkylthio or aryl; ##STR128## represents a radical of formula ##STR129## wherein each X independently represents S, S(.dbd.O) or S(.dbd.O).sub.2 ; R.sup.4 and R.sup.5 each independently represent hydrogen, hydroxy, halo, cyano, nitro, amino, C.sub.1-6 alkyl, hydroxyC.sub.1-6 alkyl, haloC.sub.1-6 alkyl, C.sub.1-6 alkyloxy, formyl, carboxyl, mono- or di(C.sub.1-6 alkyl)amino, C.sub.1-6 alkyloxycarbonyl or aryl;
- --R.sup.6 --R.sup.7 -- represents a bivalent radical of formula:
- --CR.sup.9 .dbd.CR.sup.9 --CR.sup.9 .dbd.CR.sup.9 -- (b-1);
- wherein each R.sup.9 independently represents hydrogen, hydroxy, halo, nitro, amino, C.sub.1-6 alkyl, hydroxyC.sub.1-6 alkyl, haloC.sub.1-6 alkyl, C.sub.1-6 alkyloxy, formyl, carboxyl, mono- or di(C.sub.1-6 alkyl)amino, C.sub.1-6 alkyloxycarbonyl or aryl; and
- aryl represents phenyl or phenyl substituted with one, two or three substituents selected from hydroxy, halo, cyano, amino, mono- or di(C.sub.1-6 alkyl)amino, C.sub.1-6 alkyl, haloC.sub.1-6 alkyl, hydroxyC.sub.1-6 alkyl, C.sub.1-6 alkyloxy, formyl, carboxyl and C.sub.1-6 alkylcarbonyl; or two adjacent carbon atoms on said phenyl may be substituted by a single bivalent radical having the formula C.sub.1-12 alkanediyl or haloC.sub.1-12 alkanediyl.
- 2. A compound according to claim 1, wherein
- R.sup.1 represents hydrogen, C.sub.1-6 alkyl or aryl;
- R.sup.2 represents hydrogen; C.sub.1-12 alkyl; C.sub.3-7 cycloalkyl; C.sub.2-8 alkenyl; aryl; or C.sub.1-12 alkyl substituted with one or two substituents selected from C.sub.3-7 cycloalkyl, hydroxy, C.sub.1-4 alkyloxy, cyano, amino, mono- and di(C.sub.1-4 alkyl)amino, mono- and di(aryl)amino, arylC.sub.1-4 alkylamino, (C.sub.1-4 alkyl) (arylC.sub.1-4 alkyl)amino, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, perhydro-azepinyl, carboxyl, C.sub.1-4 alkyloxycarbonyl, aminocarbonyl, mono- and di(C.sub.1-4 alkyl)aminocarbonyl, aryl, aryloxy and arylthio; ##STR130## represents a radical of formula (a) or (b) wherein R.sup.4 and R.sup.5 each independently represent hydrogen, hydroxy, halo, nitro, amino, C.sub.1-6 alkyl, hydroxyC.sub.1-6 alkyl, haloC.sub.1-6 alkyl, C.sub.1-6 alkyloxy, formyl, carboxyl, mono- or di(C.sub.1-6 alkyl)amino, C.sub.1-6 alkyloxycarbonyl or aryl.
- 3. A compound according to claim 1, wherein
- R.sup.1 represents hydrogen, hydroxy, C.sub.1-6 alkyl;
- R.sup.2 represents hydrogen; C.sub.1-12 alkyl; C.sub.3-7 cycloalkyl; pyrrolidinyl optionally substituted with C.sub.1-4 alkyl or C.sub.1-4 alkyloxycarbonyl; aryl or C.sub.1-12 alkyl substituted with one or two substituents selected from hydroxy, C.sub.1-4 alkyloxy, mono- and di(C.sub.1-4 alkyl)amino, (C.sub.1-4 alkyl) (arylC.sub.1-4 alkyl)amino, C.sub.1-4 alkyloxycarbonyl, morpholinyl, piperidinyl, piperazinyl optionally substituted with C.sub.1-4 alkyl, and aryloxy;
- R.sup.3 represents hydrogen and C.sub.1-6 alkyl;
- Het represents imidazolyl optionally substituted with C.sub.1-6 alkyl; pyridinyl or triazolyl; ##STR131## represents a radical of formula (a) or (b), wherein: X represents S;
- R.sup.4 and R.sup.5 each independently represent hydrogen, hydroxy, nitro, cyano, amino, C.sub.1-6 alkyl or aryl;
- --R.sup.6 --R.sup.7 -- represents a bivalent radical of formula (b-1), wherein each R.sup.9 independently represents hydrogen, C.sub.1-6 alkyl, hydroxy, halo, amino, haloC.sub.1-6 alkyl or C.sub.1-6 -alkyloxy.
- 4. A compound according to claim 1, wherein Het is 1-imidazolyl optionally substituted with C.sub.1-6 alkyl or aryl; 2-imidazolyl optionally substituted with C.sub.1-6 alkyl; 5-imidazolyl optionally substituted with C.sub.1-6 alkyl; 1,3,4-triazol-1-yl and 1,2,4-triazol-1-yl.
- 5. A compound according to claim 1, wherein ##STR132## represents a radical of formula (b), wherein X represents S; and --R.sup.6 --R.sup.7 -- represents a bivalent radical of formula (b-1).
- 6. A compound according to claim 1, wherein R.sup.2 represents C.sub.1-12 alkyl; C.sub.3-7 cycloalkyl; aryl or C.sub.1-12 alkyl substituted with mono- or di(C.sub.1-4 alkyl)amino, C.sub.1-4 alkyloxycarbonyl or aryloxy.
- 7. A compound according to claim 1, wherein the compound is
- N-[4-[2-ethyl-1(1H-imidazol-1-yl)butyl]phenyl]-2-benzothiazolamine;
- N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-2-benzothiazolamine;
- N-[4-[2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]-2-benzothiazolamine;
- N-[4-[2-(dimethylamino)-1-(1H-1,2,4-triazol-1-yl)propyl]phenyl]-2-benzothiazolamine;
- N-[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl]phenyl]-6-methoxy-2-benzothiazolamine;
- N-[4-[2-(dimethylamino)-1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-2-benzothiazolamine;
- N-[4-[2-(dimethylamino)-2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]phenyl]-2-benzothiazolamine;
- N-[4-[cyclohexyl(1H-imidazol-1-yl)methyl]phenyl]-2-benzothiazolamine;
- N-[4-[cyclohexyl(1H-1,2,4-triazol-1-yl)methyl]phenyl]-2-benzothiazolamine, a N-oxide, a stereochemically isomeric form or a pharmaceutically acceptable addition salt thereof.
- 8. A composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined in claim 1.
- 9. A process of preparing a composition comprising intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound as defined in claim 1.
- 10. A process of preparing a compound as claimed in claim 1, comprising
- a) reacting an intermediate of formula (II) ##STR133## wherein R.sup.1 to R.sup.3 and ##STR134## are defined as in claim 1, and W.sup.1 is an appropriate leaving group, with Het-H (III) or a functional derivative thereof, wherein Het is defined as in claim 1, in a reaction-inert solvent and in the presence of a suitable base, and optionally, in the presence of triphenylphosphine and diethyl azodicarboxylate;
- b) N-alkylation of an intermediate of formula (IV) ##STR135## wherein R.sup.1 to R.sup.3 and Het are defined as in claim 1, with an intermediate of formula (V) ##STR136## wherein ##STR137## is defined as in claim 1 and W.sup.2 is an appropriate leaving group, in a reaction-inert solvent;
- c) reacting an intermediate of formula (VI) ##STR138## wherein R.sup.1 to R.sup.3 and Het are defined as in claim 1, with an intermediate of formula (VII) or a functional derivative thereof, ##STR139## wherein R.sup.4 and R.sup.5 are defined as in claim 1 and W.sup.3 is an appropriate leaving group, in a reaction-inert solvent and optionally in the presence of an acid, thus forming a compound of formula (I-a-1) ##STR140## d) reacting an intermediate of formula (VIII) ##STR141## wherein R.sup.1, R.sup.2 and Het are defined as in claim 1, with an intermediate of formula (IX-1) ##STR142## wherein --R.sup.6 --R.sup.7 -- is defined as in claim 1, in a reaction-inert solvent, thus forming an intermediate of formula (I-b-1) ##STR143## e) reacting an intermediate of formula (VIII) ##STR144## wherein R.sup.1, R.sup.2 and Het are defined as in claim 1, with an intermediate of formula (IX-2) ##STR145## wherein --R.sup.5 is defined as in claim 1, in a reaction-inert solvent, thus forming an intermediate of formula (I-a-2) ##STR146## f) reacting an intermediate of formula (X) ##STR147## wherein R.sup.1, R.sup.2 and Het are defined as in claim 1, with an intermediate of formula (IX-1) in a reaction-inert solvent and in the presence of a suitable base, thus forming a compound of formula (I-b-1);
- g) reacting an intermediate corresponding to a compound of formula (I) wherein R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form a carbonyl group, with Het-H (III) whereby Het is defined as in claim 1, in the presence of an appropriate reagent, in a reaction-inert solvent, and optionally in the presence of chlorotriethylsilane, thus forming a compound of formula (I) wherein R.sup.1 is hydroxy;
- h) reacting an intermediate corresponding to a compound of formula (I) wherein R.sup.2 is L-C.sub.1-12 alkyl wherein L is an appropriate leaving group, with C.sub.1-4 alkylO.sup.- M.sup.+ wherein M.sup.+ is a suitable metal ion, in a suitable solvent, thus forming a compound of formula (I) wherein R.sup.2 is C.sub.1-4 alkyloxyC.sub.1-12 alkyl;
- i) reducing an intermediate corresponding to a compound of formula (I) wherein said R.sup.2 is connected to the carbon atom bearing the R.sub.2 substituent by a double bond using a suitable reducing agent, in a suitable solvent, thus forming a compound of formula (I) wherein R.sup.2 is optionally substituted C.sub.1-12 alkyl;
- and if desired, converting compounds of formula (I) into each other following art-known transformations, and further, if desired, converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment with an acid, or into a therapeutically active non-toxic base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; and also, if desired, preparing stereochemically isomeric forms or N-oxide forms thereof.
- 11. A method of treating a warm-blooded animal suffering from a disease characterized by an abnormal proliferation and/or abnormal differentiation of normal, preneoplastic or neoplastic cells comprising administering to the warm-blooded animal a retinoic mimetic amount of a compound of claim 1.
- 12. The method of claim 11, wherein the disease is selected from cancer or psoriasis.
Priority Claims (1)
Number |
Date |
Country |
Kind |
96201781 |
Jun 1996 |
EPX |
|
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a National Stage application under 35 U.S.C. .sctn. 371 of PCT/EP97/03248 filed Jun. 19, 1997, which claims priority from EP 96.201.781.0, filed Jun. 27, 1996.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/EP97/03248 |
6/19/1997 |
|
|
4/29/1999 |
4/29/1999 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO97/49704 |
12/31/1997 |
|
|
Foreign Referenced Citations (3)
Number |
Date |
Country |
0 260 744 A3 |
Mar 1988 |
EPX |
0 260 744 A2 |
Mar 1988 |
EPX |
0 371 559 A2 |
Jun 1990 |
EPX |