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Claims for Patent: 4,316,839

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Claims for Patent: 4,316,839

Title: Imidazodiazepine derivatives
Abstract:Imidazodiazepine derivatives of the formula ##STR1## wherein A together with the two carbon atoms denoted as .alpha. and .beta. is selected from the group consisting of ##STR2## the dotted line represents the double bond present in groups (a) and (b), D is >C.dbd.O or >C.dbd.S, R.sup.1 is selected from the group consisting of cyano, lower alkanoyl and a group of the formula --COOR.sup.4, R.sup.4 is selected from the group consisting of methyl, ethyl, isopropyl and 2-hydroxyethyl, R.sup.5 is selected from the group consisting of hydrogen, trifluoromethyl and halogen and R.sup.6 is selected from the group consisting of hydrogen, trifluoromethyl, halogen and lower alkyl and either R.sup.2 is hydrogen and R.sup.3 is hydrogen or lower alkyl or R.sup.2 and R.sup.3 together are trimethylene or propenylene and the carbon atom denoted as .gamma. has the S- or R,S-configuration, and pharmaceutically acceptable salts thereof are presented and have utility for antagonizing the central-depressant, muscle relaxant, ataxic, blood pressure-lowering and respiratory-depressant properties of 1,4-benzodiazepines which have tranquillizing activity. They can be used, for example, as antidotes in the case of intoxications in which excessive intake of 1,4-benzodiazepines which have tranquillizing participates, or for shortening an anaesthesia induced by such 1,4-benzodiazepines. They can also be used for suppressing the activities on the central nervous system of 1,4-benzodiazepines used in other fields of indication, for example of schistosomicidally-active 1,4-benzodiazepines such as (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2 -one. Also presented are processes to produce the imidazodiazepine derivatives and intermediates therefor.
Inventor(s): Gerecke; Max (Reinach, CH), Haefely; Willy (Reinach, CH), Hunkeler; Walter (Magden, CH), Kyburz; Emilio (Reinach, CH), Mohler; Hanns (Inzlingen, DE), Pieri; Lorenzo (Riehen, CH), Polc; Petar (Binningen, CH)
Assignee: Hoffman-La Roche Inc. (Nutley, NJ)
Application Number:06/193,775
Patent Claims: 1. A compound of the formula ##STR31## wherein A together with the two carbon atoms denoted as .alpha. and .beta. is selected from the group consisting of ##STR32## the dotted line represents the double bond present in groups (a) and (b), D is >C.dbd.O or >C.dbd.S, R.sup.1 is selected from the group consisting of cyano, lower alkanoyl and a group of the formula --COOR.sup.4, R.sup.4 is selected from the group consisting of methyl, ethyl, isopropyl and 2-hydroxyethyl, R.sup.5 is selected from the group consisting of hydrogen, trifluoromethyl and halogen and R.sup.6 is selected from the group consisting of hydrogen, trifluoromethyl, halogen and lower alkyl and either R.sup.2 is hydrogen and R.sup.3 is hydrogen or lower alkyl or R.sup.2 and R.sup.3 together are trimethylene or propenylene and the carbon atom denoted as .gamma. has the S- or R,S-configuration,

and pharmaceutically acceptable acid addition salts thereof.

2. The compound of claim 1, wherein A together with the two carbon atoms denoted as .alpha. and .beta. is the group (a) defined in claim 1 and the dotted line is the double bond present in this group, D is >C.dbd.O or >C.dbd.S, R.sup.1 is a group of the formula --COOR.sup.4, R.sup.2 is hydrogen, R.sup.3 is hydrogen or lower alkyl, R.sup.4 is methyl, ethyl or isopropyl and R.sup.5 and R.sup.6 both are hydrogen.

3. The compound of claim 1, wherein A together with the two carbon atoms denoted as .alpha. and .beta. is the group (a) defined in claim 1 and the dotted line is the double bond present in this group, D is >C.dbd.O or >C.dbd.S, R.sup.1 is a group of the formula --COOR.sup.4, R.sup.2 and R.sup.3 together are trimethylene and the carbon atom denoted as .gamma. has the S-configuration, R.sup.4 is methyl, ethyl or isopropyl and R.sup.5 and R.sup.6 both are hydrogen.

4. The compound of claim 1, wherein A together with the two carbon atoms denoted as .alpha. and .beta. is the group (a) defined in claim 1 and the dotted line is the double bond present in this group, D is >C.dbd.O or >C.dbd.S, R.sup.1 is a group of the formula --COOR.sup.4, R.sup.2 is hydrogen, R.sup.3 is hydrogen or lower alkyl, R.sup.4 is methyl, ethyl or isopropyl, R.sup.5 is halogen and R.sup.6 is hydrogen.

5. The compound of claim 1, wherein A together with the two carbon atoms denoted as .alpha. and .beta. is the group (a) defined in claim 1 and the dotted line is the double bond present in this group, D is >C.dbd.O or >C.dbd.S, R.sup.1 is a group of the formula --COOR.sup.4, R.sup.2 and R.sup.3 together are trimethylene and the carbon atom denoted as .gamma. has the S-configuration, R.sup.4 is methyl, ethyl or isopropyl, R.sup.5 is fluorine and R.sup.6 is hydrogen.

6. The compound of claim 1, wherein R.sup.1 is cyano or a group of the formula --COOR.sup.4 in which R.sup.4 is methyl, ethyl or isopropyl.

7. The compound of claim 6, wherein R.sup.3 is methyl when R.sup.2 is hydrogen.

8. The compound of claim 6, wherein the carbon atom denoted as .gamma. in formula I has the S-configuration when R.sup.2 and R.sup.3 together are trimethylene.

9. The compound of claim 8, wherein A together with the two carbon atoms denoted as .alpha. and .beta. are the group (a) defined in claim 1 and the dotted line represents the double bond present in this group, R.sup.5 is hydrogen or fluorine and R.sup.6 is hydrogen, fluorine, chlorine or methyl with at least one of R.sup.5 and R.sup.6 representing hydrogen.

10. The compound: Ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3 -carboxylate.

11. The compound: Ethyl 7-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3 -carboxylate.

12. The compound: Ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3 -carboxylate.

13. The compound: Ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c] [1,4]benzodiazepine-1-carboxylate.

14. The compound: Ethyl (R,S)-11,13a-dihydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazep ine-1-carboxylate.

15. The compound: Ethyl 8-fluoro-11,13a-dihydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodia zepine-1-carboxylate.

16. A compound selected from the group consisting of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxyl ate; methyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxyl ate; isopropyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxyl ate; methyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3 -carboxylate; isopropyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-6H-imidazo[1,5-a][1,4]benzodiazepine-3 -carboxylate; ethyl 5,6-dihydro-5,7-dimethyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carb oxylate; ethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benz odiazepine-1-carboxylate; methyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benz odiazepine-1-carboxylate; isopropyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benz odiazepine-1-carboxylate; ethyl (S)-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c] [1,4]-benzodiazepine-1-carboxylate; ethyl (S)-11,12,13,13a-tetrahydro-8-methyl-9-oxo-9H-imidazo[1,5-a]pyrrolo-[2,1-c ][1,4]benzodiazepine-1-carboxylate; ethyl 5,6-dihydro-5-methyl-6-thioxo-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carb oxylate; ethyl 8-fluoro-5,6-dihydro-5-methyl-6-thioxo-4H-imidazo[1,5-a][1,4]-benzodiazepi ne-3-carboxylate; 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3 -carbonitrile; (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benz odiazepine-1-carbonitrile; 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonit rile; methyl (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]-pyrrolo[1,2-a]thieno[3 ,2-e][1,4]diazepine-1-carboxylate; ethyl (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3, 2-e][1,4]diazepine-1-carboxylate; ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3- carboxylate and methyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3- carboxylate.

17. The compound: Ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3 -carboxylate and pharmaceutically acceptable acid addition salts thereof.
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