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Last Updated: March 29, 2024

Claims for Patent: 5,468,743


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Summary for Patent: 5,468,743
Title: Imidazo[2,1-b]benzazepine derivatives, compositions and method of use
Abstract:The present invention is concerned with novel imidazo[2, 1-b][3]benzazepines of formula ##STR1## the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein each of the dotted lines independently represents an optional bond; R.sup.1 represents hydrogen, halo, C.sub.1-4 alkyl or C.sub.1-4 alkyloxy; R.sup.2 represents hydrogen, halo, C.sub.1-4 alkyl or C.sub.1-4 alkyloxy; R.sup.3 represents hydrogen, C.sub.1-4 alkyl, ethenyl substituted with hydroxycarbonyl or C.sub.1-4 alkyloxycarbonyl, C.sub.1-4 alkyl substituted with hydroxycarbonyl or C.sub.1-4 alkyloxycarbonyl, hydroxyC.sub.1-4 alkyl, formyl or hydroxycarbonyl; R.sup.4 represents hydrogen, C.sub.1-4 alkyl, hydroxyC.sub.1-4 alkyl, phenyl or halo; R.sup.5 represents hydrogen, C.sub.1-4 alkyl or halo; L represents hydrogen; C.sub.1-6 alkyl; C.sub.1-6 alkyl substituted with one substituent selected from the group consisting of hydroxy, halo, C.sub.1-4 alkyloxy, hydroxycarbonyl, C.sub.1-4 alkyloxycarbonyl, C.sub.1-4 alkyloxycarbonyl-C.sub.1-4 alkyloxy, hydroxycarbonylC.sub.1-4 alkyloxy, C.sub.1-4 alkyloxycarbonylamino, C.sub.1-4 alkylaminocarbonyl, C.sub.1-4 alkylaminocarbonylamino, C.sub.1-4 alkylaminothiocarbonylamino, aryl, aryloxy and arylcarbonyl; C.sub.1-6 alkyl substituted with both hydroxy and aryloxy; C.sub.3-6 alkenyl; C.sub.3-6 alkenyl substituted with aryl; or, L represents a radical of formula --Alk--Y--Het.sup.1 (a-1),--Alk--NH--CO--Het.sup.2 (a-2)or --Alk--Het.sup.3 (a-3); provided that 6,11-dihydro-11-(4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine is ecxluded, which are useful antiallergic compounds. Compositions comprising said compounds, methods of using and processes for preparing the same.
Inventor(s): Janssens; Frans E. (Bonheiden, BE), Diels; Gaston S. M. (Ravels, BE), Leenaerts; Joseph E. (Rijkevorsel, BE)
Assignee: Janssen Pharmaceutica N.V. (Beerse, BE)
Application Number:08/142,474
Patent Claims: 1. A compound of the formula: ##STR159## a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein:

each of the dotted lines independently represents an optional bond;

R.sup.1 represents hydrogen, halo, C.sub.1-4 alkyl, or C.sub.1-4 alkyloxy;

R.sup.2 represents hydrogen, halo, C.sub.1-4 alkyl, or C.sub.1-4 alkyloxy;

R.sup.3 represents hydrogen, C.sub.1-4 alkyl, ethenyl substituted with hydroxycarbonyl or C.sub.1-4 alkyloxycarbonyl, C.sub.1-4 alkyl substituted with hydroxycarbonyl or C.sub.1-4 alkyloxycarbonyl, hydroxyC.sub.1-4 alkyl, formyl or hydroxycarbonyl;

R.sup.4 represents hydrogen, C.sub.1-4 alkyl, hydroxyC.sub.1-4 alkyl, phenyl or halo;

R.sup.5 represents hydrogen, C.sub.1-4 alkyl or halo;

L represents C.sub.1-6 alkyl; C.sub.1-6 alkyl substituted with one substituent selected from the group consisting of hydroxy, halo,

C.sub.1-4 alkyloxy, hydroxycarbonyl, C.sub.1-4 alkyloxycarbonyl, C.sub.1-4 alkyloxycarbonylC.sub.1-4 alkyloxy, hydroxycarbonylC.sub.1-4 alkyloxy, C.sub.1-4 alkyloxycarbonylamino, C.sub.1-4 alkylaminocarbonyl, C.sub.1-4 alkylaminocarbonylamino, C.sub.1-4 alkylaminothiocarbonylamino, aryl, aryloxy and arylcarbonyl; C.sub.1-6 alkyl substituted with both hydroxy and aryloxy; C.sub.3-6 alkenyl; C.sub.3-6 alkenyl substituted with aryl;

wherein each aryl is phenyl or phenyl substituted with halo, cyano, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkyloxy, aminocarbonyl or phenyl substituted with C.sub.1-4 alkyloxycarbonyl or hydroxycarbonyl; or

L represents a radical of the formula:

Alk represents C.sub.1-4 alkanediyl;

Y represents O, S or NH;

Het.sup.1, Het.sup.2 and Het.sup.3 each represent:

furanyl, thienyl, oxazolyl, thiazolyl or imidazolyl each optionally substituted with one or two C.sub.1-4 alkyl substituents;

pyrrolyl or pyrazolyl optionally substituted with formyl, hydroxyC.sub.1-4 alkyl, hydroxycarbonyl, C.sub.1-4 alkyloxycarbonyl or with one or two C.sub.1-4 alkyl substituents;

thiadiazolyl or oxadiazolyl optionally substituted with amino or C.sub.1-4 alkyl;

pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl each optionally substituted with C.sub.1-4 alkyl, C.sub.1-4 alkyloxy, amino, hydroxy or halo; or

imidazo[4,5-c]pyridin-2-yl;

and Het.sup.3 may also represent a member selected from the group consisting of:

(a) 4,5-dihydro-5-oxo-1H-tetrazolyl substituted with C.sub.1-4 alkyl;

(b) 2-oxo-3-oxazolidinyl;

(c) 2,3-dihydro-2-oxo-1H-benzimidazol1-yl; and

(d) a radical of the formula: ##STR160## wherein: R.sup.6 represents hydrogen or C.sub.1-4 alkyl; and

A-Z represents --S--CH.dbd.CH--, --S--CH.sub.2 --CH.sub.2 --, --S--CH.sub.2 --CH.sub.2 --CH.sub.2 --, --CH.dbd.CH--CH.dbd.CH--, --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --, --N(CH.sub.3)--C(CH.sub.3).dbd.CH-- or --CH.dbd.C (CH.sub.3)--O--.

2. A compound according to claim 1 wherein L is C.sub.1-4 alkyl or C.sub.1-4 alkyl substituted with hydroxycarbonyl or C.sub.1-4 alkyloxycarbonyl.

3. A compound according to claim 1 wherein:

R.sup.3 represents hydrogen, C.sub.1-4 alkyl, formyl, hydroxyC.sub.1-4 alkyl or hydroxycarbonyl;

R.sup.4 represents hydrogen, halo or hydroxyC.sub.1-4 alkyl; and

L represents C.sub.1-4 alkyl, haloC.sub.1-4 alkyl, hydroxycarbonylC.sub.1-4 alkyl, C.sub.1-4 alkyloxycarbonylC.sub.1-4 alkyl, C.sub.1-4 alkyloxycarbonylaminoC.sub.1-4 alkyl, arylC.sub.1-4 alkyl, propenyl, or

L is a radical of the formula:

Het.sup.1, Het.sup.2 and Het.sup.3 each represent furanyl oxazolyl, or thiazolyl each optionally substituted with C.sub.1-4 alkyl; thiadiazolyl optionally substituted with amino; pyridinyl; pyrimidinyl optionally substituted with hydroxy; or imidazo[4,5-c]pyridin-2-yl;

or Het.sup.3 may also represent a radical of the formula (b-2): ##STR161##

4. A compound according to claim 3 wherein

R.sup.1 represents hydrogen or halo;

R.sup.2 represents hydrogen, halo or C.sub.1-4 alkyloxy; and

L represents hydrogen, C.sub.1-4 alkyl, haloC.sub.1-4 alkyl, hydroxycarbonylC.sub.1-4 alkyl, C.sub.1-4 alkyloxycarbonylC.sub.1-4 alkyl, or a radical of formula (a-1), wherein Y represents NH.

5. A compound according to claim 1 wherein said compound is selected from the group consisting of

5,6-dihydro-11-(1-methyl-4-piperidinylidene)-11H-imidazo[2,1-b][3 ]benzazepine;

9-fluoro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3] benzazepine;

11-(1-methyl-4-piperidinylidene)-11H-imidazo[2,1-b][3]benzazepine;

6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepi ne-3-methanol;

8-fluoro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3] benzazepine;

6,11-dihydro-11-(1-methyl-4-piperidinylidene)- 5H-imidazo[2,1-b][3]benzazepine-3-carboxaldehyde;

6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepi ne-3carboxylic acid;

7-fluoro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3] benzazepine; and

4-(8-fluoro-5,6-dihydro-11H-imidazo[2,1-b][3]benzazepin-11-ylidene)-1-piper idinepropanoic acid dihydrate.

6. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound as defined in claim 1 and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound as defined in claim 2 and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound as defined in claim 3 and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound as defined in claim 4 and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound as defined in claim 5 and a pharmaceutically acceptable carrier.

11. A method of treating allergic conditions in warm blooded animals which comprises administering to warm blooded animals suffering from allergic conditions an effective anti-allergic amount of a compound as defined in claim 1.

12. A method of treating allergic conditions in warm blooded animals which comprises administering to warm blooded animals suffering from allergic conditions an effective anti-allergic amount of a compound as defined in claim 2.

13. A method of treating allergic conditions in warm blooded animals which comprises administering to warm blooded animals suffering from allergic conditions an effective anti-allergic amount of a compound as defined in claim 3.

14. A method of treating allergic conditions in warm blooded animals which comprises administering to warm blooded animals suffering from allergic conditions an effective anti-allergic amount of a compound as defined in claim 4.

15. A method of treating allergic conditions in warm blooded animals which comprises administering to warm blooded animals suffering from allergic conditions an effective anti-allergic amount of a compound as defined in claim 5.

16. A compound of the formula: ##STR162## an acid addition salt thereof or a stereochemically isomeric form thereof, wherein each of the dotted lines independently represents an optional bond, and wherein:

R.sup.1 represents hydrogen, halo, C.sub.1-4 alkyl or C.sub.1-4 alkyloxy;

R.sup.2 represents hydrogen, halo, C.sub.1-4 alkyl or C.sub.1-4 alkyloxy;

R.sup.3 represents hydrogen, C.sub.1-4 alkyl, ethenyl substituted with hydroxycarbonyl or C.sub.1-4 alkyloxycarbonyl, C.sub.1-4 alkyl substituted with hydroxycarbonyl or C.sub.1-4 alkyloxycarbonyl, hydroxyC.sub.1-4 alkyl, formyl or hydroxycarbonyl;

R.sup.4 represents hydrogen, C.sub.1-4 alkyl, hydroxyC.sub.1-4 alkyl, phenyl or halo;

R.sup.5 represents hydrogen, C.sub.1-4 alkyl or halo; and

Q represents phenyloxycarbonyl, or C.sub.1-6 alkyl substituted with a member selected from the group consisting of halo, cyano, amino, isothiocyanato, (4-amino-3-pyridinyl)aminothiocarbonylamino, (CH.sub.3 O).sub.2 CH--CH.sub.2 --NH--C(.dbd.NCH.sub.3)--NH--, and methylsulfonyloxy.

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