US5646146A
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US
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Heterocyclic compounds and their preparation and use
Assignee: Novo Nordisk AS
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Filing: 1995-05-25
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Granted: 1997-07-08
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Expires: 2015-05-25
Abstract
Abstract The present invention relates to 9H-indeno[1,2-b]pyrazin-3(4H)-ones and 9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-diones or tautomeric forms thereof which are useful in treating neurological and psychiatric diseases based on the antagonism of the glycine binding site on the NMDA receptor complex.
Inventors
- 👤 Peter Faarup
- 👤 Palle Jakobsen
- 👤 Anker Steen J.o slashed.rgensen
- 👤 Henrik Klitgaard
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-31 21:24
CPC Classifications
C; C07; C07D; C07D241/00; C07D241/36; C07D241/38; A; A61; A61P; A61P25/00; A61P25/26; C07F; C07F9/00; C07F9/02; C07F9/547; C07F9/645; C07F9/6509; C07F9/650952; C07F9/650994
Claims Analysis
Total Claims: 33
Claim 1
Independent Claim
187 words
A compound of formula (I) or a tautomeric form thereof ##STR24## wherein R 1 , R 2 , R 3 and R 4 independently are hydrogen, halogen, C 1-6 -alkyl or C 1-6 -alkoxy; and R 5 is hydrogen; hydroxy; halogen; cyano; C 1-6 -alkyl optionally substituted with hydroxy; C 1-6 -alkoxy optionally substituted with one or two phenyl group(s) wherein the phenyl group(s) is/are optionally substituted with halogen; C 1-6 -(alkoxyalkoxy); C 1-6 -thioalkyl optionally substituted with an amino group wherein the amino group is optionally mono or disubstituted with C 1-6 -alkyl; C 1-6 -acyloxy; phosphono; C 1-6 -alkoxy disubstituted phosphonyl; or a morpholino or piperazinyl group which is optionally substituted with a C 1-6 -alkyl group wherein the alkyl group is optionally substituted by hydroxy or wherein the morpholino or piperazinyl group is optionally substituted with one or two phenyl group(s) wherein the phenyl group(s) is/are optionally substituted with methoxy; and R 6 is hydrogen, C -6 -alkyl or phenyl; or R 5 and R 6 together represent a carbonyl group, a hydroxyimino group or a benzyloxyimino group; or a pharmaceutically acceptable salt thereof.
Claim 2
Dependent Claim
187 words
A compound of formula (I) or a tautomeric form thereof ##STR24## wherein R 1 , R 2 , R 3 and R 4 independently are hydrogen, halogen, C 1-6 -alkyl or C 1-6 -alkoxy; and R 5 is hydrogen; hydroxy; halogen; cyano; C 1-6 -alkyl optionally substituted with hydroxy; C 1-6 -alkoxy optionally substituted with one or two phenyl group(s) wherein the phenyl group(s) is/are optionally substituted with halogen; C 1-6 -(alkoxyalkoxy); C 1-6 -thioalkyl optionally substituted with an amino group wherein the amino group is optionally mono or disubstituted with C 1-6 -alkyl; C 1-6 -acyloxy; phosphono; C 1-6 -alkoxy disubstituted phosphonyl; or a morpholino or piperazinyl group which is optionally substituted with a C 1-6 -alkyl group wherein the alkyl group is optionally substituted by hydroxy or wherein the morpholino or piperazinyl group is optionally substituted with one or two phenyl group(s) wherein the phenyl group(s) is/are optionally substituted with methoxy; and R 6 is hydrogen, C -6 -alkyl or phenyl; or R 5 and R 6 together represent a carbonyl group, a hydroxyimino group or a benzyloxyimino group; or a pharmaceutically acceptable salt thereof.
Claim 3
Dependent Claim
21 words
A compound according to claim 1, wherein R 1 , R 2 , R 3 and R 4 independently are H.
Claim 4
Dependent Claim
24 words
A compound according to claim 1, wherein R 5 and R 6 together represent a carbonyl group, a hydroxyimino group or a benzyloxyimino group.
Claim 5
Dependent Claim
135 words
A compound according to claim 1, wherein R 5 is hydrogen; hydroxy; halogen; cyano; C 1-6 -alkyl optionally substituted with hydroxy; C 1-6 -alkoxy optionally substituted with one or two phenyl group(s) wherein the phenyl group(s) is/are optionally substituted with halogen; C 1-6 -(alkoxyalkoxy); C 1-6 -thioalkyl optionally substituted with an amino group wherein the amino group is optionally mono or disubstituted with C 1-6 -alkyl; C 1-6 -acyloxy; phosphono; C 1-6 -alkoxy disubstituted phosphonyl; or a morpholino or piperazinyl group which is optionally substituted with a C 1-6 -alkyl group wherein the alkyl group is optionally substituted by hydroxy or wherein the morpholino or piperidinyl group is optionally substituted with one or two phenyl group(s) wherein the phenyl group(s) is/are optionally substituted with methhoxy; and R 6 is hydrogen, C 1-6 -alkyl or phenyl.
Claim 6
Dependent Claim
15 words
A compound according to claim 1 which is: 9H-Indeno[1,2-b]pyrazine-2,3,9(1H,4H)-trione; or a pharmaceutically acceptable salt thereof.
Claim 7
Dependent Claim
20 words
A compound according to claim 1 which is: (E)-9-Hydroxyimino-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione; (Z)-9-Hydroxyimino-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione; (E) -9-Benzyloxyimino-9H-indeno[1,2-b]pyrazine-2,3(1H,4H) -dione; (Z)-9-Benzyloxyimino-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione; or a pharmaceutically acceptable salt thereof.
Claim 8
Dependent Claim
15 words
A compound according to claim 1 which is: 9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione; or a pharmaceutically acceptable salt thereof.
Claim 9
Dependent Claim
25 words
A compound according to claim 1 which is: 9-Hydroxy -9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione; 9-Acetoxy-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione; 9-Ethoxy-9H -indeno[1,2-b]pyrazine-2,3(1H,4H)-dione; 9-(2-Methoxyethoxy)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione; 9-(3,3-Diphenylpropoxy)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione; 9-(2,2-Bis(4-chlorophenyl))ethoxy-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione; or a pharmaceutically acceptable salt thereof.
Claim 10
Dependent Claim
17 words
A compound according to claim 1 which is: 9-(2-Aminoethylthio)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione; 9-(2-Diethylaminoethylthio)-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione; or a pharmaceutically acceptable salt thereof.
Claim 11
Dependent Claim
19 words
A compound according to claim 1 which is: 9-Dimethoxyphosphonyl-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione; 9-Diethoxyphosphonyl-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione; 9-Phosphono-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione; or a pharmaceutically acceptable salt thereof.
Claim 12
Dependent Claim
15 words
A compound according to claim 1 which is: 9-Morpholino-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione; or a pharmaceutically acceptable salt thereof.
Claim 13
Dependent Claim
20 words
A compound according to claim 1 which is: 9-(4-Methyl-1-piperazinyl)-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione; 9-(4-(2-Hydroxyethyl)-1-piperazinyl)-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione; 9-(4-(2-Methoxyphenyl)-1-piperazinyl)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione; 9-(1-Piperazinyl)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione; or a pharmaceutically acceptable salt thereof.
Claim 14
Dependent Claim
18 words
A compound according to claim 1 which is: 9-Hydroxy-9-phenyl-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione; 9-Ethoxy-9-phenyl-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione; or a pharmaceutically acceptable salt thereof.
Claim 15
Dependent Claim
18 words
A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable carrier or diluent.
Claim 16
Dependent Claim
19 words
The pharmaceutical composition according to claim 14 in the form of an oral dosage unit or parenteral dosage unit.
Claim 17
Dependent Claim
22 words
The pharmaceutical composition according to claim 15 in the form of an oral dosage unit containing about 1-200 mg of the compound.
Claim 18
Dependent Claim
203 words
A compound of formula (I) or a tautomeric form thereof ##STR25## wherein R 1 , R 2 , R 3 and R 4 independently are hydrogen, halogen, C 1-6 -alkyl or C 1-6 -alkoxy; R 5 is hydrogen; hydroxy; halogen; cyano; C 1-6 -alkyl optionally substituted with hydroxy; C 1-6 -alkoxy optionally substituted with one or two phenyl group(s) wherein the phenyl group(s) is/are optionally substituted with halogen; C 1-6 -(alkoxyalkoxy); C 1-6 -thioalkyl optionally substituted with an amino group wherein the amino group is optionally mono or disubstituted with C 1-6 -alkyl; C 1-6 -acyloxy; phosphono; C 1-6 -alkoxy disubstituted phosphonyl; or a morpholino or piperazinyl group which is optionally substituted with a C 1-6 -alkyl group wherein the alkyl group is optionally substituted by hydroxy or wherein the morpholino or piperazinyl group is optionally substituted with one or two phenyl group(s) wherein the phenyl group(s) is/are optionally substituted with methoxy; and R 6 is hydrogen, C 1-6 -alkyl or phenyl; or R 5 and R 6 together represent a carbonyl group, a hydroxyimino group or a benzyloxyimino group; and R 7 is phenyl or --CH 2 OR 8 wherein R 8 is hydrogen or benzyl; or a pharmaceutically acceptable salt thereof.
Claim 19
Dependent Claim
203 words
A compound of formula (I) or a tautomeric form thereof ##STR25## wherein R 1 , R 2 , R 3 and R 4 independently are hydrogen, halogen, C 1-6 -alkyl or C 1-6 -alkoxy; R 5 is hydrogen; hydroxy; halogen; cyano; C 1-6 -alkyl optionally substituted with hydroxy; C 1-6 -alkoxy optionally substituted with one or two phenyl group(s) wherein the phenyl group(s) is/are optionally substituted with halogen; C 1-6 -(alkoxyalkoxy); C 1-6 -thioalkyl optionally substituted with an amino group wherein the amino group is optionally mono or disubstituted with C 1-6 -alkyl; C 1-6 -acyloxy; phosphono; C 1-6 -alkoxy disubstituted phosphonyl; or a morpholino or piperazinyl group which is optionally substituted with a C 1-6 -alkyl group wherein the alkyl group is optionally substituted by hydroxy or wherein the morpholino or piperazinyl group is optionally substituted with one or two phenyl group(s) wherein the phenyl group(s) is/are optionally substituted with methoxy; and R 6 is hydrogen, C 1-6 -alkyl or phenyl; or R 5 and R 6 together represent a carbonyl group, a hydroxyimino group or a benzyloxyimino group; and R 7 is phenyl or --CH 2 OR 8 wherein R 8 is hydrogen or benzyl; or a pharmaceutically acceptable salt thereof.
Claim 20
Dependent Claim
21 words
A compound according to claim 17, wherein R 1 , R 2 , R 3 and R 4 independently are H.
Claim 21
Dependent Claim
24 words
A compound according to claim 17, wherein R 5 and R 6 together represent a carbonyl group, a hydroxyimino group or a benzyloxyimino group.
Claim 22
Dependent Claim
135 words
A compound according to claim 17, wherein R 5 is hydrogen; hydroxy; halogen; cyano; C 1-6 -alkyl optionally substituted with hydroxy; C 1-6 -alkoxy optionally substituted with one or two phenyl group(s) wherein the phenyl group(s) is/are optionally substituted with halogen; C 1-6 -(alkoxyalkoxy); C 1-6 -thioalkyl optionally substituted with an amino group wherein the amino group is optionally mono or disubstituted with C 1-6 -alkyl; C 1-6 -acyloxy; phosphono; C 1-6 -alkoxy disubstituted phosphonyl; or a morpholino or piperazinyl group which is optionally substituted with a C 1-6 -alkyl group wherein the alkyl group is optionally substituted by hydroxy or wherein the morpholino or piperidinyl group is optionally substituted with one or two phenyl group(s) wherein the phenyl group(s) is/are optionally substituted with methoxy; and R 6 is hydrogen, C 1-6 -alkyl or phenyl.
Claim 23
Dependent Claim
17 words
A compound according to claim 17 which is: 2-Phenyl-9H -indeno[1,2-b]pyrazine-3,9(4H)-dione; 2-Hydroxymethyl-9H-indeno[1,2-b]pyrazine-3,9(4H)-dione; or a pharmaceutically acceptable salt thereof.
Claim 24
Dependent Claim
18 words
A pharmaceutical composition comprising a compound according to claim 17 together with a pharmaceutically acceptable carrier or diluent.
Claim 25
Dependent Claim
19 words
The pharmaceutical composition according to claim 22 in the form of an oral dosage unit or parenteral dosage unit.
Claim 26
Dependent Claim
22 words
The pharmaceutical composition according to claim 23 in the form of an oral dosage unit containing about 1-200 mg of the compound.
Claim 27
Independent Claim
242 words
A method of treating a central nervous system ailment related to the glycine binding site on the NMDA receptor complex comprising administering to a subject in need thereof an effective amount of a compound of formula I or a tautomeric form thereof selected from the group consisting of ##STR26## wherein R 1 , R 2 , R 3 and R 4 independently are hydrogen, halogen, C 1-6 -alkyl or C 1-6 -alkoxy; R 5 is hydrogen; hydroxy; halogen; cyano; C 1-6 -alkyl optionally substituted with hydroxy; C 1-6 -alkoxy optionally substituted with one or two phenyl group(s) wherein said phenyl group(s) is/are optionally substituted with halogen; C 1-6 -(alkoxyalkoxy); C 1-6 -thioalkyl optionally substituted with an amino group wherein said amino group is optionally mono or disubstituted with C 1-6 -alkyl; C 1-6 -acyloxy; phosphono; C 1-6 -alkoxy disubstituted phosphonyl;, or a morpholina or piperazinyl group which is optionally substituted with a C 1-6 -alkyl group wherein said alkyl group is optionally substituted by hydroxy or wherein the morphalina or piperazinyl group is optionally substituted with one or two phenyl group(s) wherein said phenyl group(s) is/are optionally substituted with methoxy; and R 6 is hydrogen, C 1-6 -alkyl or phenyl; or R 5 and R 6 together represent a carbonyl group, a hydroxyimino group or a benzyloxyimino group; and R 7 is hydrogen, phenyl or --CH 2 OR 8 wherein R 8 is hydrogen or benzyl; or a pharmaceutically acceptable salt thereof.
Claim 28
Independent Claim
242 words
A method of treating a central nervous system ailment related to the glycine binding site on the NMDA receptor complex comprising administering to a subject in need thereof an effective amount of a compound of formula I or a tautomeric form thereof selected from the group consisting of ##STR26## wherein R 1 , R 2 , R 3 and R 4 independently are hydrogen, halogen, C 1-6 -alkyl or C 1-6 -alkoxy; R 5 is hydrogen; hydroxy; halogen; cyano; C 1-6 -alkyl optionally substituted with hydroxy; C 1-6 -alkoxy optionally substituted with one or two phenyl group(s) wherein said phenyl group(s) is/are optionally substituted with halogen; C 1-6 -(alkoxyalkoxy); C 1-6 -thioalkyl optionally substituted with an amino group wherein said amino group is optionally mono or disubstituted with C 1-6 -alkyl; C 1-6 -acyloxy; phosphono; C 1-6 -alkoxy disubstituted phosphonyl;, or a morpholina or piperazinyl group which is optionally substituted with a C 1-6 -alkyl group wherein said alkyl group is optionally substituted by hydroxy or wherein the morphalina or piperazinyl group is optionally substituted with one or two phenyl group(s) wherein said phenyl group(s) is/are optionally substituted with methoxy; and R 6 is hydrogen, C 1-6 -alkyl or phenyl; or R 5 and R 6 together represent a carbonyl group, a hydroxyimino group or a benzyloxyimino group; and R 7 is hydrogen, phenyl or --CH 2 OR 8 wherein R 8 is hydrogen or benzyl; or a pharmaceutically acceptable salt thereof.
Claim 29
Dependent Claim
16 words
A compound which is: 9-Hydroxyimino-9H-indeno[1,2-b]pyrazin-3(4H)-one; 9-Chloro-9H-indeno[1,2-b]pyrazine-3(4H)-one; 9-Hydroxy-9H-indeno[1,2-b]pyrazine-3(4H)- one; 9-Hydroxy-9-phenyl-9H-indeno[1,2-b]pyrazine-3(4H)-one; 9-Acetoxy-9-phenyl-9H-indeno[1,2-b]pyrazine-3(4H)-one; or a pharmaceutically acceptable salt thereof.
Claim 30
Dependent Claim
16 words
A compound which is: 9-Hydroxyimino-9H-indeno[1,2-b]pyrazin-3(4H)-one; 9-Chloro-9H-indeno[1,2-b]pyrazine-3(4H)-one; 9-Hydroxy-9H-indeno[1,2-b]pyrazine-3(4H)- one; 9-Hydroxy-9-phenyl-9H-indeno[1,2-b]pyrazine-3(4H)-one; 9-Acetoxy-9-phenyl-9H-indeno[1,2-b]pyrazine-3(4H)-one; or a pharmaceutically acceptable salt thereof.
Claim 31
Dependent Claim
18 words
A pharmaceutical composition comprising a compound according to claim 26 together with a pharmaceutically acceptable carrier or diluent.
Claim 32
Dependent Claim
19 words
The pharmaceutical composition according to claim 27 in the form of an oral dosage unit or parenteral dosage unit.
Claim 33
Dependent Claim
22 words
The pharmaceutical composition according to claim 28 in the form of an oral dosage unit containing about 1-200 mg of the compound.
References Cited (Backward Citations)
US4889855A
Cited
US4912108A
Cited
US5026704A
Cited
US5081123A
Cited
US5153195A
Cited
US5182279A
Cited
EP0511152A2
Cited
WO1995026342A1
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 2000-07-07 | 2001-01-06 | 2001-07-08 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2004-07-07 | 2005-01-06 | 2005-07-08 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2008-07-07 | 2009-01-06 | 2009-07-08 | $7700.00 | Window Closed / Lapsed |