# US 9,040,524 B2 · Antifungal 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]-benzodiazepines and 6H-pyrrolo[1,2-a][1,4]benzodiazepines substituted with bicycle benzene derivatives

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- Number: US 9,040,524 B2
- Document ID: US9040524B2
- Status: Granted
- Kind: B2
- Application number: 13/995,526
- Filed: 2011-12-19
- Published: 2013-10-10
- Granted: 2015-05-26
- Earliest claimed: 2010-12-21
- Assignees: Janssen Pharmaceutica NV
- Applicants: Lieven Meerpoel; Louis Jules Roger Marie Maes; Kelly de Wit
- Inventors: Lieven Meerpoel; Louis Jules Roger Marie Maes; Kelly de Wit
- Web page: https://patentgrep.com/patent/US9040524B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 31/10: Antimycotics
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is concerned with novel antifungal 5,6-dihydro-4H-pyrrolo-[1,2-a][1,4]benzodiazepines and 6H-pyrrolo[1,2-a][1,4]benzodiazepines substituted with bicyclic benzene derivatives of Formula (I) wherein R1, R2, R3, R4, R5, R6 and R7 have the meaning defined in the claims. The compounds according to the present invention are active mainly against dermatophytes and systemic fungal infections. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

## Claims

### Claim 1

A compound of formula (I)
or a stereoisomeric form thereof, wherein
R1 is hydrogen, halo, C1-4alkyl or C1-4alkyloxy;
R2 is hydrogen or halo;
R3 and R4 are hydrogen;
or R3 and R4 taken together form a bond;
R5 is hydrogen or C1-4alkyloxy;
R6 and R7 taken together form a bivalent radical —R6-R7—, having formula:
—(CH2)m—Y1—(CH2)n-m— (a),
—(CH2)n-m—Y1—(CH2)m— (b),
—(CH2)s— (c),
—Y2a—(CH2)t—Y2b— (d), or
—(CH2)r—Y2a—CH2—Y2b—(CH2)q— (e);
wherein the bivalent radical —R6-R7— may, where possible, be substituted with one or more substituents selected from the group consisting of halo, C1-4alkyl, hydroxyl, C1-4alkyloxy and oxo;
Y1 represents O, NR8a or S;
Y2a and Y2b each independently represent O, NR8b or S;
R8a represents hydrogen or C1-4alkyl;
R8b represents hydrogen or C1-4alkyl;
m represents 0, 1 or 2;
n represents 2, 3 or 4;
s represents 3, 4 or 5;
t represents 1, 2 or 3;
r represents 0 or 1;
q represents 0 or 1;
provided that at least one of r and q is 1;
or a pharmaceutically acceptable addition salt thereof;
provided that the compound is not 4-(1,3-benzodioxol-5-yl)-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine or 4-(1,3-benzodioxol-5-yl)-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine HCl.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein
R6 and R7 taken together form a bivalent radical —R6-R7—, having formula:
—(CH2)m—Y1—(CH2)n-m— (a),
—(CH2)n-m—Y1—(CH2)m— (b),
—(CH2)s— (c),or
—Y2a—(CH2)t—Y2b— (d),
wherein the bivalent radical —R6-R7— may, where possible, be substituted with one or more substituents selected from the group consisting of halo, C1-4alkyl and oxo;
Y1 represents O or NR8a;
Y2a and Y2b each independently represent O or NR8b;
R8a represents hydrogen or C1-4alkyl;
R8b represents hydrogen or C1-4alkyl;
m represents 0, 1 or 2;
n represents 2 or 3;
s represents 3 or 4;
t represents 1.

### Claim 3 (depends on 1)

The compound according to claim 1 wherein
R1 is hydrogen, halo or C1-4alkyloxy;
R6 and R7 taken together form a bivalent radical —R6-R7—, having formula:
—(CH2)m—Y1—(CH2)n-m— (a),
—(CH2)n-m—Y1—(CH2)m— (b),
—(CH2)s— (c), or
—Y2a—(CH2)t—Y2b— (d);
wherein the bivalent radical —R6-R7— may, where possible, be substituted with one or more substituents selected from the group consisting of halo, C1-4alkyl and oxo;
Y1 represents O or NH;
Y2a represents O;
Y2b represent O or NH;
m represents 0, 1 or 2;
n represents 2 or 3;
s represents 3 or 4;
t represents 1.

### Claim 4 (depends on 1)

The compound according to claim 1 wherein
R1 is halo;
R2 is hydrogen;
R5 is hydrogen;
R6 and R7 taken together form a bivalent radical —R6-R7—, having formula:
—(CH2)m—O—(CH2)n-m—,
—(CH2)s—, or
—O—CH2—O—;
wherein the bivalent radical —(CH2)m—O—(CH2)n-m— or —(CH2)s— may, where possible, be substituted with one or more substituents selected from the group consisting of halo and oxo;
wherein the bivalent radical —O—CH2—O— is substituted with one or more substituents selected from the group consisting of halo and oxo;
m represents 0 or 1;
n represents 3;
s represents 3 or 4.

### Claim 5 (depends on 1)

The compound according to claim 1 wherein R1 is halo.

### Claim 6 (depends on 1)

The compound according to claim 1 wherein R6 and R7 taken together form a bivalent radical —R6-R7—, wherein —R6-R7— is selected from the group consisting of —(CH2)3—, —(CH2)4—, —(CH2)2—O—, —CH2—CH(CH3)—O—, —C(═O)—(CH2)2—, —C(═O)—(CH2)3—, —O—(CH2)2—, —O—(CH2)3—, —CH2—O—(CH2)2—, —(CH2)2—C(═O)—, —O—CF2—(CH2)2—, —(CH2)2—C(═O)—, —CF2—(CH2)2—, —C(═O)—O—CH2—, —CH2—O—C(═O)—, —O—CF2—O—, —O—C(═O)—N(CH3)—, —N(CH3)—(CH2)2—, and —N(CH3)—C(═O)—C(CH3)2—.

### Claim 7 (depends on 1)

The compound according to claim 1 wherein R6 and R7 taken together form a bivalent radical —R6-R7— having the formula —O—CH2—O—,
wherein —O—CH2—O— is substituted with one or two substituents selected from the group consisting of halo, C1-4alkyl, hydroxyl, C1-4alkyloxy and oxo.

### Claim 8 (depends on 1, 2, 3, 4, 5, 6, 7)

The compound according to any one of claims 1 to 7 wherein
R3 and R4 are taken together to form a bond.

### Claim 9 (depends on 1)

The compound according to claim 1 wherein the compound is
7-chloro-4-(2,3-dihydro-1H-inden-5-yl)-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzo-diazepine,
7-chloro-4-(2,3-dihydro-1H-inden-S-yl)-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzo-diazepine HCl,
7-chloro-4-(2,3-dihydro-1H-inden-S-yl)-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzo-diazepine HBr,
7-chloro-4-(2,3-dihydro-1H-inden-S-yl)-6H-pyrrolo[1,2-a][1,4]benzodiazepine,
7-chloro-4-(5,6,7,8-tetrahydro-2-naphthalenyl)-6H-pyrrolo[1,2-a][1,4]benzodiazepine,
7-chloro-4-(2,2-difluoro-1,3-benzodioxol-5-yl)-6H-pyrrolo[1,2-a][1,4]benzodiazepine,
4-(2,2-difluoro-1,3-benzodioxol-5-yl)-7,9-difluoro-6H-pyrrolo[1,2-a][1,4]benzo-diazepine,
4-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-fluoro-6H-pyrrolo[1,2-a][1,4]benzodiazepine,
6-(7-fluoro-6H-pyrrolo[1,2-a][1,4]benzodiazepin-4-yl)-3,4-dihydro-1(2H)-naphthalenone,
7-chloro-4-(2,2-difluoro-3,4-dihydro-2H-1-benzopyran-6-yl)-6H-pyrrolo[1,2-a][1,4]-benzodiazepine,
4-(3,4-dihydro-1H-2-benzopyran-6-yl)-7-fluoro-6H-pyrrolo[1,2-a][1,4]benzodiazepine,
7-chloro-4-(3,4-dihydro-1H-2-benzopyran-6-yl)-6H-pyrrolo[1,2-a][1,4]benzodiazepine,
9-chloro-4-(2,2-difluoro-1,3-benzodioxol-5-yl)-6H-pyrrolo[1,2-a][1,4]benzodiazepine, or 10-chloro-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-6H-pyrrolo[1,2-a][1,4]benzo-diazepine,
a stereoisomeric form thereof,
or a pharmaceutically acceptable addition salt thereof.

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 1)

A method for treating a patient having a fungal infection, said method comprising administering to said patient a therapeutically effective amount of a compound of claim 1.

### Claim 12 (depends on 11)

The method according to claim 11 wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Candida spp.; Aspergillus spp.; Cryptococcus neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum spp.; Trichophyton spp; Fusarium spp.; Rhizomucor spp.; Mucor circinelloides; Rhizopus spp.; Malassezia furfur; Acremonium spp.; Paecilomyces; Scopulariopsis; Arthrographis spp.; Scytalidium; Scedosporium spp.; Trichoderma spp.; Penicillium spp.; Penicillium marneffei; Blastoschizomyces.

### Claim 13 (depends on 11)

The method according to claim 11 wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Candida parapsilosis, Aspergillus spp., Cryptococcus neoformans, Microsporum spp., and Trichophyton spp.

### Claim 14 (depends on 11)

The method according to claim 11 wherein the fungal infection is caused by one or more of the fungi selected from the group consisting of Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum and Aspergillus fumigates.